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Molecular Environment Effects That Modulate the Photophysical Properties of Novel 1,3-Phosphinoamines Based on 2,1,3-Benzothiadiazole

We report synthesis, crystal structure, and photophysical properties of novel 1,3-phosphinoamines based on 4-amino-2,1,3-benzothiadiazole (NH2-btd): Ph2PCH(Ph)NH-btd (1) and Ph2P(E)CH(Ph)NH-btd, (E = O (2α and 2β·thf), S (3), Se (4)). Chalcogenides 2–4 exhibit bright emissions with a major band at 519–536 nm and a minor band at 840 nm. According to TD-DFT calculations, the first band is attributed to fluorescence, while the second band corresponds to phosphorescence. In the solid state, room temperature quantum yield reaches 93% in the case of the sulphide. The compounds under study feature effects of the molecular environment on the luminescent properties, which manifest themselves in fluorosolvatochromism as well as in a luminescent response to changes in crystal packing and in contributions to aggregation effects. Specifically, transformation of solid 2β·thf to solvate-free 2β either by aging or by grinding causes crystal packing changes, and, as a result, a hypsochromic shift of the emission band. Polystyrene films doped with 2 reveal a bathochromic shift upon increasing the mass fraction from 0.2 to 3.3%, which is caused by molecular aggregation effects.

Introduction
Molecular environment effects appear as an intriguing phenomenon that give rise to unique photophysical properties of compounds both in the solid state and in solution, e.g., mechanochromism [1], solvatochromism [2], aggregation-induced emission [2], etc. These properties open up prospects for the design of smart materials for sensors, [3] optoelectronic devices [4], and biological labelling [5]. For these purposes, 2,1,3-benzothiadiazole (btd) derivatives have been extensively studied owing to the prospects for their applications in organic light-emitting diodes [6], luminescent sensors [7], and bioimaging [5]. Further functionalization of btds provides a way to tune the electronic properties of the heterocyclic moiety that mainly contributes to the frontier orbitals. Importantly, btd derivatives feature secondary bonding interactions, such as chalcogen bonding and π-π stacking [8], which can govern molecular environment effects. Studies of such effects in btds, e.g., aggregationinduced emission [9][10][11][12], are rapidly evolving nowadays.
On the other hand, 1,3-aminophosphines comprising {P-C-N} moiety represent a wide class of organic compounds that can be synthesized with a variation of well-known multicomponent "phospha-Mannich" reactions [13][14][15]. The introduction of various substituents is possible both at the N and P and also at the C atoms of the backbone moiety, which opens up wide possibilities for the design of such derivatives [16]. Still, a large family of 2 of 13 1,3-aminophosphines containing a sulphur-nitrogen aromatic substituent at the N atom remain unexplored. To date, only a couple of works have been devoted to the synthesis of related thiazole derivatives [17,18]. The corresponding 1,3-aminophosphines based on btd are currently unknown, although we recently reported a number of related btd-based phosph(III)azanes and their non-trivial photophysical properties [19,20].
In continuation of our work, we describe the synthesis and structure of a novel 1,3-phosphinoamine and its chalcogenides (O, S, and Se) bearing the btd substituent as a promising chromophore group as well as study their photophysical properties with special emphasis on molecular environment effects. The photophysical properties of the compounds were interpreted by means of quantum chemical methods (TD-DFT).

General Procedures
All manipulations for the syntheses were performed using standard Schlenk technique and a glovebox. The solvents were purified using standard technique and stored under argon atmosphere. 4-amino-2,1,3-benzothiadiazole was prepared as reported previously [21]. Benzaldehyde was distilled under argon before use. Diphenylphosphine was used as received. Elemental analyses were performed on various MICRO cube instrument for C, H, N, and S elements. IR-spectra were recorded on a Fourier IR spectrometer FT-801 (Simex) in KBr pellets ( Figure S1, Supplementary Materials). 1 H NMR spectra (500.13 MHz) and 31 P NMR spectra (202.45 MHz) were taken with a Bruker DRX-500 spectrometer in dry CDCl 3 or C 6 D 6 at room temperature; the solvent peak was used as the internal reference.
Thick (ca. 40 µm) films of 2 in polystyrene were prepared by coating a solution of a given amount of 2 in 100 µL of polystyrene/toluene solution (concentration of polystyrene is 36.5 mg/mL) on a glass plate, followed by drying.
The diffuse reflectance UV-vis spectra of solid samples were obtained with a Shimadzu UV-3101 spectrophotometer at room temperature. Samples for the diffuse reflectance measurements were prepared by a thorough grinding of a mixture of the compounds under study (about 0.01 mol fraction) with BaSO 4 , which was used also as a standard. Spectral dependences of the diffuse reflectance were converted into spectra of a Kubelka-Munk function. Emission and excitation spectra of solids were recorded at 298 and 77 K on a Fluorolog 3 spectrometer (Horiba Jobin Yvon, Paris, France) equipped with cooled PC177CE-010 photon detection module with a PMT R2658 photomultiplier. Excitation and emission spectra were corrected for source intensity (lamp and grating) and emission spectral response (detector and grating) by standard correction curves. For the measurements, powdered samples were placed between two nonfluorescent quartz plates. The emission decay curves were recorded on the same instrument using TCSPC (time-correlated single photon counting) technique. Laser diode was used as an excitation source. The curves were fitted by either one or two exponential decay; the fit yielded the emission lifetime values. Absolute PL quantum yields (QY) for the solids were recorded using Quanta-ϕ device of Fluorolog 3.
UV-vis spectra of the solutions in 1 cm quartz cuvettes in argon atmosphere and of the films in air were obtained with Agilent Cary 60 spectrometer (Agilent Technologies, Santa Clara, CA, USA). Emission and excitation spectra of the same solutions (in the transmittance mode) and films (in the reflection mode) were recorded on an Agilent Cary Eclipse spectrometer (Agilent Technologies, Santa Clara, CA, USA). The quantum yields of the samples in toluene solutions were determined relative to 4-amino-2,1,3-benzothiadiazole (QY = 12%).
For the photobleaching experiment, solid sample 3 was constantly irradiated in air conditions with a luminescent 6 W lamp for 12 h. The luminescence spectra were recorded on an Agilent Cary Eclipse spectrometer.

X-ray Data
Single-crystal XRD data for compounds 1, 2β·thf, and 4 (Table S1) were collected  with a Bruker D8 Venture diffractometer with a CMOS PHOTON III detector and IµS 3.0 microfocus source (MoK α radiation (λ = 0.71073 Å), collimating Montel mirrors). Singlecrystal XRD data for compounds 2α and 3 were collected with a Bruker Apex DUO diffractometer (Karlsruhe, Germany) equipped with a 4 K CCD area detector and a graphitemonochromated sealed tube (MoK α radiation). All the data were collected at 150 K. The crystal structures were solved using the SHELXT [22] and were refined using SHELXL [23] programs with OLEX2 GUI [24]. Atomic displacement parameters for non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed geometrically with the exception for those at the amino groups, which were localized from the residual electron density map and refined with the restrain on N-H bond (0.88 Å). The structures of 1-3 were deposited to the Cambridge Crystallographic Data Centre (CCDC) as a supplementary publication, No. 2170844-2170848.
Hirshfeld promolecular surfaces mapped over Shape Index were plotted with the Crystal Explorer (version 17.5) program [25]. The intermolecular interaction energies between pairs of molecules in the crystal were also estimated using the Crystal Explorer program with the geometry determined by single-crystal XRD with corrected C-H (1.08 Å) and N-H (1.00 Å) bond lengths at DFT B3LYP/6-31G(d,p) level.
Powder XRD data for compounds 1, 2α, 3, and 4 (Figures S2-S5) were collected at room temperature with a Bruker D8 Advance diffractometer. The data for 2β·thf and its transformation product upon drying were collected at 150 K by a Bruker D8 Venture diffractometer ( Figure S6). In all cases, CuK α radiation was used.

Quantum-Mechanical Calculations
All calculations were performed using Orca 4.2.1 package (Wiley Interdiscip, Hudson, NJ, USA). Ground-state geometries were optimized by DFT method with PBE0-D3(BJ) functional. Geometries of S 1 and T 1 states were optimized with same functional by TD-DFT and unrestricted DFT methods respectively. Geometry optimizations were performed in vacuum without any constraints. Frequencies were calculated for all geometries at the same states. Optimized geometries correspond to a minimum at PES, since no negative frequencies were found. Excitation spectra were calculated by TDA-DFT with (triplet states) and without Tamm-Dancoff approximation. In all calculations def2-TZVP(-f) and auxiliary def2/J and def2-TZVP/C (for TD-DFT) basis sets were used. Crystals of compound 1 suitable for single-crystal XRD study were grown by recrystallization of the product from Et 2 O.  Crystals of compounds 3 and 4 were grown by recrystallization of the products from hot THF.

Syntheses and Crystal Structures
One-pot condensation of diphenylphospine, benzaldehyde, and 4-amino-2,1,3benzothaidiazole in anhydrous THF at ambient conditions yielded α-aminophosphine 1 (Scheme 1). The corresponding chalcogenides 2-4 were obtained by in situ oxidizing of 1 with H 2 O 2 or elemental chalcogens. For the reaction with H 2 O 2 , the solvent was removed in vacuum and replaced by acetonitrile due to risk of formation of explosive peroxides. Crystalline compounds were purified by recrystallization from Et 2 O or THF and were characterized by 1 H, 31 P NMR spectroscopy and elemental analysis.

Syntheses and Crystal Structures
One-pot condensation of diphenylphospine, benzaldehyde, and 4-amino-2,1,3-benzothaidiazole in anhydrous THF at ambient conditions yielded α-aminophosphine 1 (Scheme 1). The corresponding chalcogenides 2-4 were obtained by in situ oxidizing of 1 with H2O2 or elemental chalcogens. For the reaction with H2O2, the solvent was removed in vacuum and replaced by acetonitrile due to risk of formation of explosive peroxides. Crystalline compounds were purified by recrystallization from Et2O or THF and were characterized by 1 H, 31 P NMR spectroscopy and elemental analysis.

Scheme 1. Synthesis of 1-4.
In the special case of the phosphinoxide derivative, we isolated two crystalline modifications, 2α and 2β·thf. The first one is formed as plate-like crystals upon concentration of THF, ethanol, or aceronitrile solution, or upon addition of n-hexane to THF solution ( Figure S7). The second modification, 2β·thf, is formed as needle crystals upon diffusion of n-hexane to saturated THF solution in a narrow period of time. Aging of the crystals of 2β·thf under the mother liquor for several days causes transformation to compound 2α. Fine crystalline phase 2β·thf is stable on air for ca. 15 min; after that, it starts losing solvate thf molecules, gradually transforming through a number of related phases to a structurally different solvate-free phase, 2β, as evidenced by powder XRD analysis ( Figure 1). The complete transformation takes place within a week. Unfortunately, the poor quality of the 2β crystals did not allowed us to solve the structure, although Pawley refinement using powder XRD gave crystal lattice with expectedly smaller unit cell volume compared to the pristine 2β·thf ( Figure S6). Note that the XRD pattern of aged 2β does not correspond to that of 2α. The crystal-to-crystal transformation between 2α and 2β does not proceed, since the mutual orientation of the molecules in 2α and 2β·thf strongly differs (see the discussion below).

Scheme 1. Synthesis of 1-4.
In the special case of the phosphinoxide derivative, we isolated two crystalline modifications, 2α and 2β·thf. The first one is formed as plate-like crystals upon concentration of THF, ethanol, or aceronitrile solution, or upon addition of n-hexane to THF solution ( Figure S7). The second modification, 2β·thf, is formed as needle crystals upon diffusion of n-hexane to saturated THF solution in a narrow period of time. Aging of the crystals of 2β·thf under the mother liquor for several days causes transformation to compound 2α. Fine crystalline phase 2β·thf is stable on air for ca. 15 min; after that, it starts losing solvate thf molecules, gradually transforming through a number of related phases to a structurally different solvate-free phase, 2β, as evidenced by powder XRD analysis ( Figure 1). The complete transformation takes place within a week. Unfortunately, the poor quality of the 2β crystals did not allowed us to solve the structure, although Pawley refinement using powder XRD gave crystal lattice with expectedly smaller unit cell volume compared to the pristine 2β·thf ( Figure S6). Note that the XRD pattern of aged 2β does not correspond to that of 2α. The crystal-to-crystal transformation between 2α and 2β does not proceed, since the mutual orientation of the molecules in 2α and 2β·thf strongly differs (see the discussion below). According to the XRD analysis, compound 2α crystallizes in the chiral space group P21; the molecule possesses chirality at the central C atom determined as R for the selected single crystal. Since the starting reagents are achiral, both S and R enantiomers likely form equally, so that the particular chirality of the crystals 2α is random. Compound 2β·thf crystallizes in the achiral space group Pbca, comprising both S and R molecules in the structure. Molecular geometries of the phosphinoamines in 2α and 2β·thf are quite similar (Figure 2), while their mutual orientation in the crystals is different. In 2α, the molecule lies above translationally equivalent one thus arranging in -A-A-sequence along a direction (Figure 3a). In 2β·thf, the corresponding molecules relating via the glide plane arrange According to the XRD analysis, compound 2α crystallizes in the chiral space group P2 1 ; the molecule possesses chirality at the central C atom determined as R for the selected single crystal. Since the starting reagents are achiral, both S and R enantiomers likely form equally, so that the particular chirality of the crystals 2α is random. Compound 2β·thf crystallizes in the achiral space group Pbca, comprising both S and R molecules in the structure. Molecular geometries of the phosphinoamines in 2α and 2β·thf are quite similar (Figure 2), while their mutual orientation in the crystals is different. In 2α, the molecule lies above translationally equivalent one thus arranging in -A-A-sequence along a direction (Figure 3a). In 2β·thf, the corresponding molecules relating via the glide plane arrange in -A-B-stack. According to Hirshfeld surface analysis [25], both molecules exhibit similar shape; the area of contacting surfaces for the two molecules are similar for 2α (ca. 70 Å 2 ) and 2β·thf (ca. 80 Å 2 ), while in the latter, they interact more strongly with each other ( Table S2)  According to the XRD analysis, compound 2α crystallizes in the chiral space grou P21; the molecule possesses chirality at the central C atom determined as R for the selecte single crystal. Since the starting reagents are achiral, both S and R enantiomers likely form equally, so that the particular chirality of the crystals 2α is random. Compound 2β·th crystallizes in the achiral space group Pbca, comprising both S and R molecules in th structure. Molecular geometries of the phosphinoamines in 2α and 2β·thf are quite simila (Figure 2), while their mutual orientation in the crystals is different. In 2α, the molecul lies above translationally equivalent one thus arranging in -A-A-sequence along a direc tion (Figure 3a). In 2β·thf, the corresponding molecules relating via the glide plane arrang in -A-B-stack. According to Hirshfeld surface analysis [25], both molecules exhibit sim lar shape; the area of contacting surfaces for the two molecules are similar for 2α (ca. 7 Å 2 ) and 2β·thf (ca. 80 Å 2 ), while in the latter, they interact more strongly with each othe ( Table S2). The Hirshfeld surfaces feature a convex induced by the O atom (Figure 3b {CH} moieties of the aryl fragments organize around the convex, and {CH} of the meth ylene group points straight at the O atom.

Photophysical Properties
The UV-Vis spectra were measured of 1-4 in the solid state and in toluene solution (Figure 4a,b, Table 1). All the compounds exhibit a similar shape of the spectra that reveal two broad bands. According to TD-DFT calculations for the single molecules (Tables S3-S6), the long wavelength band corresponds to S 0 -S 1 transition between HOMO and LUMO orbitals (Figures 5 and S8-S11). The transition has locally excited character with a notable contribution of intramolecular charge transfer from non-bonding orbitals of P (for 1) or chalcogens (for 2-4). Upon going from 2 to 4, localization of HOMO orbitals on chalcogenide atom increases, i.e., the non-bonding character of HOMO-LUMO transition increases by the rise of chalcogen weight. The maximum of the bands in the solid state (445-460 nm) bathochromically shifts compared to the solution (403-409), which implies influence of the immediate environment of the molecules on the photophysical properties of 1-4. Notably, the calculated wavelength for S 0 -S 1 transition well agrees with the experiment in the case of the solutions of 2-4 and is slightly overestimated for the solution of 1. The short wavelength band at ca. 310 nm is attributed to π-π* transition in the btd moiety. The short wavelength band at ca. 310 nm is attributed to π-π* transition in the btd moiety.   Table 1. Calculated in vacuum wavelengths for S0-S1, S1-S0, and T1-S0 transitions (nm), experimental absorption (λabs) and emission (λEm) maxima (nm), emission lifetime at the given temperature (τ, ns) and quantum yield (QY, %; the excitation at 420 nm) for compounds 1-4 in the solid state and toluene solution.

Calculated
Toluene Solution Solid State S0-S1 S1-S0    Compounds 1-4 at room temperature reveal photoluminescence (PL) both in the solid state and toluene solution, characterized by a major band with the excitation-independent maximum of 519-538 nm (Figure 6a,b). According to TD-DFT calculations, the band corresponds to S1-S0 transition between frontier orbitals; the calculated wavelengths well agree with the experiment (Tables 1 and S7). The frontier orbitals in S1-geometry state resemble those in S0 state, featuring for the HOMO a slight loss of the electron density at the chalcogen atom in favour of the phenyl moiety at the C atom ( Figures S12-S15). The nature of the chalcogen at P atom slightly affects the position of the band. The PL intensity in toluene rises in the series 1-2-3 and then falls for 4. This tendency persists for absolute quantum yields for the solid compounds ( Table 1). The reduced intensity for 4 is likely associated with the heavy Se atom effect that causes emission quenching. The emission kinetics for the major band of the solids ( Figure S16) can be fitted either one (in the case of 4) or two exponential decay (in the case of 2 and 3; for 1, we failed to evaluate the parameters due to the poor emission intensity). The presence of two components may indicate the existence of different emission aggregates that originate from some features of solids, e.g., defects and surface characteristics, inclusions, among others. In all the cases, the emission lifetime lies in a nanosecond range of 4-20 ns implying the major band corresponds to a fluorescence. We have performed the photobleaching experiment on the example of solid 3: upon continuous irradiation of the compound with a visible light on air, the emission intensity gradually drops by ca. 10% in 12 h ( Figure S17).
In the solutions, the excitation spectra resemble the absorption spectra, indicating a straightforward relaxation process to the lowest excited state. In the solid state, the relaxation process is less straightforward due to the appearance of solid-state effects, e.g., a relatively strong electron-phonon coupling [26], and extrinsic features (inclusions and defects). As a result, nonradiative decay rates for the relaxation from different excited states can vary, which leads to some differences in the absorption and excitation spectra, i.e., the flattened profile of the latter. Compounds 1-4 at room temperature reveal photoluminescence (PL) both in the solid state and toluene solution, characterized by a major band with the excitation-independent maximum of 519-538 nm (Figure 6a,b). According to TD-DFT calculations, the band corresponds to S 1 -S 0 transition between frontier orbitals; the calculated wavelengths well agree with the experiment (Tables 1 and S7). The frontier orbitals in S 1 -geometry state resemble those in S 0 state, featuring for the HOMO a slight loss of the electron density at the chalcogen atom in favour of the phenyl moiety at the C atom ( Figures S12-S15). The nature of the chalcogen at P atom slightly affects the position of the band. The PL intensity in toluene rises in the series 1-2-3 and then falls for 4. This tendency persists for absolute quantum yields for the solid compounds ( Table 1). The reduced intensity for 4 is likely associated with the heavy Se atom effect that causes emission quenching. The emission kinetics for the major band of the solids ( Figure S16) can be fitted either one (in the case of 4) or two exponential decay (in the case of 2 and 3; for 1, we failed to evaluate the parameters due to the poor emission intensity). The presence of two components may indicate the existence of different emission aggregates that originate from some features of solids, e.g., defects and surface characteristics, inclusions, among others. In all the cases, the emission lifetime lies in a nanosecond range of 4-20 ns implying the major band corresponds to a fluorescence. We have performed the photobleaching experiment on the example of solid 3: upon continuous irradiation of the compound with a visible light on air, the emission intensity gradually drops by ca. 10% in 12 h ( Figure S17). Apart the major band, the PL spectra of solid 2-4 reveal a weak but notable band in the IR range peaked at ca. 840 nm. Although the experimental emission lifetime was not determined for the IR band due to the poor emission intensity, we can attribute the minor band to a phosphorescence. Indeed, the calculated wavelength for T1-S0 transition well agrees with the experiment (Tables 1 and S7). The intersystem crossing (ISC) promotion to T1 state is likely achieved from S1 state, which is facilitated by the presence of n-electron chalcogenide groups at the P atom. However, due to the similar nature of S1 and T1 states (Figures S12-S15 , Table S8), in accordance with the El'Sayed rule [27], the ISC is rather inefficient, which results in a low intensity of the emission at 840 nm. Upon cooling from room temperature to 77K, the emission bands for the solid compounds do not change their position while showing some increase in intensity ( Figure S18). Note that in the toluene solutions, no signal above the noise in the IR range was observed. The quenching of the phosphorescence upon going from the solid state to the solution can be a consequence of a facilitated intramolecular motion in the latter, which results in increased probability of radiationless transitions. Thus, we interpret the phenomenon of induced solid-state phosphorescence in terms of Restriction of Intramolecular Motion (RIM), which is proposed as a mechanism of aggregation-induced emission (AIE) [28].
Interestingly, pristine crystalline compound 2β·thf shows a bathochromic shift of the major band by 10 nm compared to 2α. Upon drying, 2β·thf transforms to solvate-free compound 2β, which reveals the same position of the band as 2α (Figures 6a and S19). Such a behaviour can be rationalized by the loss of contacts of the phosphinoamine with thf molecules and/or by changing its contacts with the neighbouring phosphinoamine molecules, which cause slight changes in the electronic structure of the molecule.
To further study the influence of the immediate molecular environment on the photophysical properties, we measured UV-Vis and PL spectra of solutions of 1 in n-hexane, THF and toluene (Figure 7a,b). PL maxima show increase in the maxima in the series: nhexane (520 nm), toluene (537 nm,) and THF (553 nm). This tendency agrees with the rise in polarity of the solvents and corresponds to the positive solvatochromism [29]. In addition, the THF: n-hexane (v/v = 1:3) mixture for 1 gives the intermediate maximum of 536 nm between those in pure n-hexane and THF ( Figure S20). In the solutions, the excitation spectra resemble the absorption spectra, indicating a straightforward relaxation process to the lowest excited state. In the solid state, the relaxation process is less straightforward due to the appearance of solid-state effects, e.g., a relatively strong electron-phonon coupling [26], and extrinsic features (inclusions and defects). As a result, nonradiative decay rates for the relaxation from different excited states can vary, which leads to some differences in the absorption and excitation spectra, i.e., the flattened profile of the latter.
Apart the major band, the PL spectra of solid 2-4 reveal a weak but notable band in the IR range peaked at ca. 840 nm. Although the experimental emission lifetime was not determined for the IR band due to the poor emission intensity, we can attribute the minor band to a phosphorescence. Indeed, the calculated wavelength for T 1 -S 0 transition well agrees with the experiment (Tables 1 and S7). The intersystem crossing (ISC) promotion to T 1 state is likely achieved from S 1 state, which is facilitated by the presence of n-electron chalcogenide groups at the P atom. However, due to the similar nature of S 1 and T 1 states (Figures S12-S15 , Table S8), in accordance with the El'Sayed rule [27], the ISC is rather inefficient, which results in a low intensity of the emission at 840 nm. Upon cooling from room temperature to 77K, the emission bands for the solid compounds do not change their position while showing some increase in intensity ( Figure S18). Note that in the toluene solutions, no signal above the noise in the IR range was observed. The quenching of the phosphorescence upon going from the solid state to the solution can be a consequence of a facilitated intramolecular motion in the latter, which results in increased probability of radiationless transitions. Thus, we interpret the phenomenon of induced solid-state phosphorescence in terms of Restriction of Intramolecular Motion (RIM), which is proposed as a mechanism of aggregation-induced emission (AIE) [28].
Interestingly, pristine crystalline compound 2β·thf shows a bathochromic shift of the major band by 10 nm compared to 2α. Upon drying, 2β·thf transforms to solvate-free compound 2β, which reveals the same position of the band as 2α (Figures 6a and S19). Such a behaviour can be rationalized by the loss of contacts of the phosphinoamine with thf molecules and/or by changing its contacts with the neighbouring phosphinoamine molecules, which cause slight changes in the electronic structure of the molecule.
To further study the influence of the immediate molecular environment on the photophysical properties, we measured UV-Vis and PL spectra of solutions of 1 in n-hexane, THF and toluene (Figure 7a,b). PL maxima show increase in the maxima in the series: n-hexane (520 nm), toluene (537 nm,) and THF (553 nm). This tendency agrees with the rise in polarity of the solvents and corresponds to the positive solvatochromism [29]. In addition, the THF: n-hexane (v/v = 1:3) mixture for 1 gives the intermediate maximum of 536 nm between those in pure n-hexane and THF ( Figure S20). In the case that the luminescent properties are sensitive to the immediate molecular environment, a substance can exhibit aggregation effects upon increasing its doping concentration in a matrix. To find whether these effects appear in our case, we prepared thick polymeric polystyrene films doped with 2 with the mass fraction varied from 0.2 to 3.3%. As expected, the films show a linear dependence of the absorption at 425 nm on the fraction of 2 (Figure 8a). The luminescence spectrum of the film with the highest doping resembles that of the solid 2α while showing a gradual shift of the band from 535 to 516 nm (Figure 8b) with the doping decrease. This phenomenon is apparently associated with the effect of aggregation of phosphinoamine molecules in films, which results in a bathochromic shift with increasing concentration. Such a shift can accompany aggregation effects as reported in works on the aggregation-induced phenomenon [30]. Positions of the emission band do not change after a week. We can exclude that the shift of the band is associated with the concentration quenching effects, since the excitation at the short wavelength side of the emission band (e.g., at 480 nm) still contributes to an intense emission, being even higher for high-doped films than for low-doped ones ( Figure S21).  In the case that the luminescent properties are sensitive to the immediate molecular environment, a substance can exhibit aggregation effects upon increasing its doping concentration in a matrix. To find whether these effects appear in our case, we prepared thick polymeric polystyrene films doped with 2 with the mass fraction varied from 0.2 to 3.3%. As expected, the films show a linear dependence of the absorption at 425 nm on the fraction of 2 (Figure 8a). The luminescence spectrum of the film with the highest doping resembles that of the solid 2α while showing a gradual shift of the band from 535 to 516 nm (Figure 8b) with the doping decrease. This phenomenon is apparently associated with the effect of aggregation of phosphinoamine molecules in films, which results in a bathochromic shift with increasing concentration. Such a shift can accompany aggregation effects as reported in works on the aggregation-induced phenomenon [30]. Positions of the emission band do not change after a week. We can exclude that the shift of the band is associated with the concentration quenching effects, since the excitation at the short wavelength side of the emission band (e.g., at 480 nm) still contributes to an intense emission, being even higher for high-doped films than for low-doped ones ( Figure S21). In the case that the luminescent properties are sensitive to the immediate molecular environment, a substance can exhibit aggregation effects upon increasing its doping concentration in a matrix. To find whether these effects appear in our case, we prepared thick polymeric polystyrene films doped with 2 with the mass fraction varied from 0.2 to 3.3%. As expected, the films show a linear dependence of the absorption at 425 nm on the fraction of 2 (Figure 8a). The luminescence spectrum of the film with the highest doping resembles that of the solid 2α while showing a gradual shift of the band from 535 to 516 nm (Figure 8b) with the doping decrease. This phenomenon is apparently associated with the effect of aggregation of phosphinoamine molecules in films, which results in a bathochromic shift with increasing concentration. Such a shift can accompany aggregation effects as reported in works on the aggregation-induced phenomenon [30]. Positions of the emission band do not change after a week. We can exclude that the shift of the band is associated with the concentration quenching effects, since the excitation at the short wavelength side of the emission band (e.g., at 480 nm) still contributes to an intense emission, being even higher for high-doped films than for low-doped ones ( Figure S21).

Conclusions
In summary, we synthesized and characterized a novel 1,3-phosphinoamine (1) bearing 4-amino-2,1,3-benzothaidiazole moiety and its oxide (2), sulphide (3), and selenide (4). For 2, two pseudopolymorphs, 2α and 2β·thf, were prepared; the latter gradually loses solvate thf molecules upon aging in air, transforming to solvate-free 2β. Compounds 1-4 reveal a major band at 519-538 nm both in the solid state and in toluene solution. Solid samples 2 and 3 feature bright emission with room-temperature absolute quantum yield of 93% for the latter. In toluene solutions, the quantum yield for 2 and 3 is close to 100%. TD-DFT investigation suggests that the band is attributed to S 1 -S 0 relaxation of a fluorescent nature; the corresponding HOMO-LUMO transition tends to increase charge-transfer contribution with the rise of chalcogen weight. This is a probable reason why solid compounds 2-4, apart from the major band in the visible region, reveal a weak band in the IR range attributed to T 1 -S 0 phosphorescence.
We studied the effects of the immediate molecular environment on the following luminescence properties: (1) Molecules of 1 show luminous sensitivity to the nature of solvent molecules (hexane, toluene, and THF), exhibiting positive fluorosolvatochromism in the corresponding solutions. (2) Phase transformation of solid 2β·thf to 2β either by aging or by grinding causes crystal packing changes, and, as a result, shift of the emission band; this opens up perspectives for stimuli-responsive effects. (3) Polystyrene films doped with 0.2 to 3.3% of 2 differ in the luminescence colour caused by molecular aggregation effects. This motivates further design of luminescent benzothiadiazoles that pave the way for developing novel fluorochromic materials.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules27123857/s1, Figure S1: IR-spectra of compounds; Figures S2-S6: Simulated and experimental powder XRD patterns; Figure S7: Photographs of crystals 2α and 2β·thf; Figure S8: Overlay of the molecules of the structures; Figures S9-S15: Frontier orbitals of the molecules in the ground and excited states; Figures S16-S18: Additional PL and excitation spectra; Figure S19: Comparison of the normalized PL spectra for compounds 2α, as-synthesized 2β·thf, and unsolvated 2β; Figure S20: PL spectra of 1 in THF, n-hexane and mixture (THF:n-hexane = 1:3), intensities normalized to relative to spectrum of n-hexane solution; Figure S21: Excitation spectra at 520 nm of polystyrene films containing 2 with a mass fraction from 0.2 to 3.3%, normalized on the long wavelength band; Table S1: Crystal data and structure refinement; Table S2: Estimated contributions to the interaction energy between a pair of the molecules; Tables S3-S6: DFT calculation of Frank-Condon excitation processes; Tables S7 and S8: DFT calculation of relaxation processes.


Novel Oxygen Fused Bicyclic Derivatives and Antioxidant Labelling: Bioactive Chalcone Based Green Synthesis

: Chalcone has become a matter of focus because of its wide variety of biological actions, such as anti-inflammation, anti-cancer, anti-tuberculosis, etc. Due to its inherent chemical reactivity, chalcone has become an easily accessible building block to construct various naturally and biologically active compounds. In modern times, the title compound is made possible to prepare through Claisen-Schmidt reaction or Aldol reaction. However, it is carried out under a conventional condition with a considerable number of variables (time, temperature, reagents, instrument parameters, etc.). In the present research work, we report a novel series of chalcone-based heterocyclic moieties along with an eco-friendly condensation reaction method permitting a ‘green approach’ to the present work. Thin-layer chromatography (TLC) was used to monitor the ’reaction’s progress, and Rf values were recorded. All of the synthesized derivative’s FTIR spectra were reported. This research focuses on seeing if green approaches can be used to synthesize the target chemical. In comparison to previous procedures, these approaches were more convenient and generated a greater yield (75-80%), showed maximum efficiency, and were stored without polluting the environment while also providing medicinal benefits. This method provides a faster reaction time, is safer for analysts, is minimal in cost, and is simple to implement. Additionally, the antioxidant activity of synthesized ligands with the DPPH assay has been studied.

Introduction
The chemistry of chalcone is very rich and is very useful nowadays that why it is gaining intense research interest globally [1,2]. Chalcone is a versatile compound that may be used to precursor various biological compounds [3]. Chalcone is electrophilic species having a ketone functional group attached to the unsaturated double bond, and due to this chromophore (CO-CH=CH) it may be able to show color [4]. Chalcone is a unique structure that consists of two aromatic rings connected by a three-carbon unsaturated carbonyl system. Due to the openchain model and the feature of skeletal modification to produce a new class of organic compounds such as azachalcones [5,6], isoxazoles [7], pyrazoles [8,9], and indole grounded chalcones [10]. Chalcone derivatives have a wide range of therapeutic properties, including anticancer, antioxidants [11], anti-inflammatory [12,13], antihypertensive [14], antimalarial [15], antiulcer [16], antiviral [17], antiprotozoal [18], cardiovascular activity [19] and mutagenic properties [20]. Chalcones are starting to synthesize many cyclic derivatives like pyrazolines, isoxazoles, pyrimidine [21,22]. Chalcone compounds have unsaturated double bonds, which delocalizes the electrons to two aromatic rings that resonate with the unsaturated double bond. Due to this phenomenon, possess a (p-electron system).
Pyrazoline is a partially reduced form of pyrazole. It is a basic five-membered heterocyclic with two neighboring nitrogen atoms within the ring and only one endocyclic double bond [23]. The electron-rich pyrazoline derivatives operate as 'Lewis's basis for complexation, resulting in a wide range of biological activities. Aside from the synthetic approach, it may be found in nature in pigments, vitamins, and plant and animal cell contents, among other things [24]. Antimicrobial [25,26], anticancer [27,28], and anti-inflammatory effects [29] are all demonstrated by pyrazoline and its substituted pyrazoline derivatives [30]. Pyrimidines are heterocyclic aromatic compounds with six members, comparable to phenyl rings. It has two nitrogen atoms arranged in six-membered rings. Various drugs containing the pyrimidine moiety are receiving a lot of interest since they represent a large class of natural and non-natural chemicals, many of which have biological functions [31].
An antioxidant is a molecule that prevents other molecules from oxidizing. Oxidation is a chemical reaction in which molecules transfer electrons or hydrogen to an oxidizing agent. Antioxidants stop these chain reactions from continuing by eliminating free radical intermediates and preventing subsequent oxidative reactions of hetero atoms [32]. Antioxidants are responsible for the 'organism's defensive mechanisms against diseases caused by free radical attacks. Plant-derived antioxidants are implicated in preventing oxidative stress-related degenerative diseases such as cancer, 'Parkinson's disease, 'Alzheimer's disease, and atherosclerosis [33].
Green chemistry is the discipline of chemistry that deals with tools, processes, and technologies that are environmentally friendly [34,35]. Chemists and chemical engineers can use it in research, development, and manufacturing to create more environmentally friendly and efficient goods that may also save money. It will now become an indispensable tool in synthetic chemistry [36,37]. 'It's a fresh approach to organic synthesis and medicinal molecule design, with significant environmental and economic benefits over classic synthetic methods [38]. Green chemistry has offered a new challenge for organic synthesis, requiring the development of novel reaction conditions that limit the usage of dangerous toxic compounds and the emission of volatile organic solvents [39]. They improve traditional procedures regarding selectivity, reaction time, and product separation and purification. Investing in techniques that reduce the need for chemical waste using alternative technologies, such as sonochemistry [40-42] and microwave technology , [43], reusable catalysts [44], renewable solvents, or even solvent-free reactions, has been attracting attention in the scientific community [45]. The synthesis of a classical Chalcone with the help of ultrasound is described in this paper. On the other hand, the model response is used to design, develop, and execute a simple and comprehensive internal quality approach for evaluating the performance of a standard ultrasonic probe.

Materials and Methods
All Chemicals, reagents, and solvent ware purchased from Sigma-Aldrich were used without further purification (simple or under vacuum distillation or recrystallization are sometimes carried out for purification). The purity of synthesized derivatives, including intermediate, was tested by thin-layer chromatography (TLC) using silica gel (60-100 mesh), chromatography was eluted using a mixture of chloroform-methanol (9.5:0.5), or chloroform-ethyl acetate (5:5), and the spots were visualized by exposure to iodine vapor. Organic solvents were distilled before use. A (1.0 mol) of 2-4 dihydroxy acetophenone and (1.0 mol) of furfural aldehyde are taken into appropriate quantity of ethanol. This solution was stirred for 10-15 minutes to maintain the temperature around 0-5°C, 15% solution of NaOH (20 ml) was added dropwise to the resulting solution within 30 minutes. This reaction mixture is stirred for 6 hrs. The TLC is used to monitor the reaction progress. After completion of the reaction. It is acidified with 30% AcOH solution. The reaction mixture was poured into ice water; the yellow solid was formed, filtered, then dried [18]. The Chalcone (CC1) was obtained according to the published method [46] (Scheme 1). Physicochemical and analytical data are presented in Table 1.

Green route method.
The ultrasound-assisted reaction was carried out in a 100 mL flask which contained a solution of (1.0 mol) 2-4 dihydroxy acetophenone and (1.0 mol) of furfural aldehyde were taken into appropriate quantity of ethanol. This solution is subjected to ultrasound irradiation. During the process, 15% NaOH (20 mL) is added dropwise within 30 minutes, and the yields vary according to the parameters used. The TLC is used to monitor the reaction progress. After completion of the reaction. It is acidified with 30% AcOH solution. The reaction mixture was poured into ice water; the yellow solid was formed, filtered, and dried. Physicochemical and analytical data are presented in Table 1. A solution of (1.0 mol) of (E)-1-(2,4-dihydroxyphenyl)-3-(furan-2-yl) prop-2-en-1-one in ethanol (25 mL) was prepared; after that, it was refluxed with (1.0 mol) of 98 % pure hydrazine hydrate derivative, guanidine and urea for 6-7 hrs., separately [47]. To give a series of compound (LL1-LL5). After completion of the reaction, the reaction mixture concentrated to its half volume; the generated solid particle was separated, then was filtered and washed with hot water and recrystallized from cold ethanol. A mixture of petroleum ether and chloroform (8:2) is used to monitor the reaction through TLC (Scheme 2) continuously. Physicochemical and analytical data are presented in Table 2.

Results and Discussion
Conventionally, chalcone can be prepared by refluxing the ketone and aldehyde in an organic solvent through Claisen-Schmidt reaction or aldol condensation as an acid or base catalyst [48,49].
The following scheme 1 depicts the synthetic techniques used to synthesize the intermediate derivative and target compounds: Another advantage of this approach is its operational simplicity, ease of work-up, and higher yield, which includes washing the mixture followed by solvent evaporation. Chalcone synthesis is a single-step process. The yields of the synthesized compounds have been shown to be significant. In the current method, we provide a mild, efficient, high-yielding approach for the condensation reaction of different aromatic ketone and furfural aldehyde. These reactions were accomplished in reduced reaction times (20-22 minutes) with high yields using this approach (80 %). The green route approach necessitates simple work-up processes, such as simple filtering to separate the products since they are -insoluble. The necessary chemicals were produced with good yields without any additional purification. Compared to the reaction time and product yield of conventional methods, this technique was chosen as green, environmentally friendly, clean, and safe to boost synthesis.

Antioxidant activity.
Free radicals are extremely reactive atoms or compounds with outermost electrons unpaired [50]. Due to the gain or loss of an unpaired electron, free radicals are continually striving to form stable bonds. The electron configuration of chalcone-based heterocyclic compounds is ready to accept/donate an electron or depends on the current oxidation state and electron configuration [13,[51][52][53]. As a result, ligands are ready to accept/donate electrons to quench radicals based on reaction conditions. The DPPH is a well-characterized synthetic solid radical that may be used to assess the antioxidant capacity of substances. The ability of ligands to reduce DPPH by receiving hydrogen or electron was measured spectrophotometrically by altering the DPPH color from yellow to brown Fig. 1. Comparing antioxidant activity with common antioxidant reference materials Quercetin and Ascorbic Acid (AA) [54,55] Fig 2-7. Even though the antioxidant activity [56,57] of CC-1 and LL1-5 is slightly lower than that of the conventional antioxidants Quercetin and Ascorbic Acid (AA), it is reasonable to believe that CC-1 and LL1-5 have the potential to be used as good antioxidant agents.      The percent DPPH radical inhibition with absorbance effect is indicated in Fig 9. Inhibition was found to be low in CC-1 compared with LL1-5, which may be because NH acts as a good oxidant that can easily react and accept/lose electrons.

Conclusions
The research work here demonstrates the synthesis of novel chemical entities of pyrazole/pyrazoline and pyrimidine derivative. Substituted pyrazoline and pyrimidine heterocyclic rings are therapeutically potential classes of compounds. The method used in the present study is one of the best methods for introducing functional group modification with ease. 'It's important to note that Chalcones have a unique template with an -unsaturated carbonyl system that allows for structural changes. The experimental results show that the ultrasound-assisted reaction is 17 times quicker than the traditional one (20 min vs. 6 hr.). The ring formation reaction of chalcone with hydrazine and its analogs to obtain substituted pyrazoline and pyrimidine heterocyclic moiety (LL1 -LL5) was attempted by employing various reagents and reaction conditions. All the desired products as a novel moiety were successfully carried out under optimized reaction conditions. In addition, the antioxidant activity of synthesized ligands wares was also successfully evaluated to show free radical scavenging activity up to 60-70 % in 30 min, which is relatively higher in comparison to other moieties.

Funding
This research received no external funding. Licochalcone A, a novel antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania.


s2fieldsofstudy: Chemistry Biology

text:
In-silico activity prediction, structure-based drug design, molecular docking and pharmacokinetic studies of selected quinazoline derivatives for their antiproliferative activity against triple negative breast cancer (MDA-MB231) cell line

Background: Cancer is a major health threat especially in unindustrialized nations. It surpasses coronary diseases and takes the number one killer position as a result of different global wide influences. Among many breast cancer substrates, triple-negative breast cancer (TNBC) is particularly devastating because it rapidly metastasize to other parts of the body, with a high risk of earlier recession and mortality. Result: In this research work, four (4) quantitative structure activity relationship (QSAR) models were developed using a series of quinazoline derivatives with activities against triple negative breast cancer cell line (MDA-MB231), model 1 was selected due to its statistical fitness with the following validation parameters: R = 0.875, Q = 0.837, R − Q = 0.038, Next test set = 5, and Rext = 0.655. Molecular docking studies was performed for the quinazoline series as well as the reference drug (Gefitinib) and the active site of the epidermal growth factor receptor (EGFR) (pdb id = 3ug2). Eight compounds (6, 10, 13, 16, 17, 18, 19 and 20) were observed to have better docking score docking scores relative to Gefitinib. Compound number nineteen from the training set (pred pIC50 = 5.67, Residual = − 0.04 and MolDock score = − 123.238) was identified as the best compound since it has the best Moldock score and was excellently predicted by the selected model with least residual value, Hence was adopted as template for the design of Ten (10) new novel compounds with better activities and better docking scores. The inhibitive activities of the designed compounds were predicted by the selected model and most of them possess an improved activity relative to the template compound (19). The designed compounds were also redocked on to active pocket of the EGFR receptor and it was observed that they displayed better docking scores compared to the Template and the reference drug (Gefitinib) utilized in the design. Furthermore, the designed compounds were subjected to ADMET and druglikeness studies using SWISSADME and pkCSM online web tools and they were observed to be pharmacologically active, easily synthesized and do not violate the Lipinski’s rule of five. Conclusion: Hence, the designed compounds can be employed as inhibitors of MDA-MB231 cell line after passing through in vivo and in vitro evaluation. © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Open Access Bulletin of the National Research Centre *Correspondence: sagirwasai@gmail.com Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B.1045, Zaria, Kaduna State, Nigeria Page 2 of 23 Abdullahi et al. Bulletin of the National Research Centre (2022) 46:2 Background Cancer is a challenging problem for the global health community, and its increasing burden necessitates seeking novel and alternatives therapies (Rajabi et  al. 2021). It takes the number one killer position as a result of different global wide influences. Although considerable progress were made in the chemotherapeutic remedy of some victims, the unrelenting obligation to the difficult task of detecting new anti-cancer drugs is still crucial. Breast cancer is the most predominant class of cancer diagnosed in females around the globe, with an incidence that intensifies vividly with age. Among many breast cancer substrates, triple-negative breast cancer (TNBC) is particularly devastating because it rapidly disperse to other parts of the body, with a high risk of earlier recession and mortality (Hu et  al. 2012). Annually, at least one million females are identified with breast tumor and TNBC is accountable for close to 15–20% of the complete breast cancer identified (Jo et al. 2019). The epidermal growth factor receptor (EGFR) plays a crucial part in the control of cell growth and is regarded as one of the most seriously evaluated tyrosine kinase’s (TK) target inhibitors (El-Azab et  al. 2010). Numerous TKs had a vital functions in cell propagation, division, metastasis and endurance, besides their uncontrolled triggering via processes such as point mutations leads to a substantial proportion of clinical cancers. EGFR is over expressed in numerous tumors, such as brain, lung, bladder, ovarian, colon, breast, head, and prostate tumors (Tiwari et al. 2015). Components of the erbB class of EGFR-TKs, which comprise of erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4), are overexpressed in a substantial ratio of human tumors, and this is attributed to the miserable prognosis of the malady (Chandregowda et al. 2009). Hence, inhibitors of erbB1 and erbB2 were acknowledged as possible anticancer drugs (Hynes and Lane 2005). Extermination of cancer cells without causing damage on other normal tissues or cells is the main purpose of anti-cancer drugs. However, the fact that some of these drugs usually destroys some other normal cells and the resistance to these drugs experienced by some patients during early period of treatment necessitates the global search for identifying new higher quality drugs that are safe for the prevention and remedy of cancer (AlSuwaidan et  al. 2016). Immediate recognition, understanding of the cause and pathway of this disorder, and improvement in remedy have played a pivotal part in curtailing breast cancer mortality rates over the past few years. Chemotherapy is still the central key to thorough therapy since it can exterminate tumor cells rapidly in the human system (Kaplan 2013). In-silico approach of drug discovery have proven to accelerate the drug discovery process, as it lessen the time taken, resources and it enables the estimation of properties of new molecules such as toxicity and efficiency even before their synthesis. A mathematical relations that are able to establish a quantitative relationship between biological activities of a molecules and their molecular structures in form of linear equation is called Quantitative Structure–Activity Relationships (QSAR) (Abdullahi et al. 2021). Efficiency and safety of the drug to the system are the two major causes leading to drug failure. Therefore, it is compulsory to find potent molecules with better ADMET properties “drug-likeliness” (Lawal et al. 2021). This research is mainly purposed in utilizing QSAR approach to compute the inhibitory activities of a series of quinazoline derivatives against MDA-MB231 breast cancer cell line, perform molecular docking studies to understand the nature of interaction between the compounds and the EGFR protein receptor, design new potent compounds based on their docking scores and examine their ADMET and drug likeness properties. Methods Data sets retrieval A series of 23 quinazoline derivatives with inhibitory activities (IC50 in μg/ml) against Triple Negative Breast cancer cell line MDA-MB231 are retrieved from Abuelizz et al. (2017). The inhibitory activities were linearized by taking their negative logarithm to base 10 as shown in Eq. 1. Chemical structure of the quinazoline analogs as well as their respective inhibitive capacity at 50% concentration (pIC50) are presented in Table 1. Calculation of molecular descriptors 2D structures of the quinazoline analogs were sketched by utilizing Chemdraw version 16.0 and they were transformed to 3D format using Spartan 14 software. Molecular mechanics force field were employed to clean the 3D structures to eliminate all strain from the structure of (1) pIC50 = −log10 ( IC50 × 10 −6 )

Page 2 of 23 Abdullahi et al. Bulletin of the National Research Centre (2022)

Background
Cancer is a challenging problem for the global health community, and its increasing burden necessitates seeking novel and alternatives therapies (Rajabi et al. 2021).
It takes the number one killer position as a result of different global wide influences. Although considerable progress were made in the chemotherapeutic remedy of some victims, the unrelenting obligation to the difficult task of detecting new anti-cancer drugs is still crucial. Breast cancer is the most predominant class of cancer diagnosed in females around the globe, with an incidence that intensifies vividly with age. Among many breast cancer substrates, triple-negative breast cancer (TNBC) is particularly devastating because it rapidly disperse to other parts of the body, with a high risk of earlier recession and mortality (Hu et al. 2012). Annually, at least one million females are identified with breast tumor and TNBC is accountable for close to 15-20% of the complete breast cancer identified (Jo et al. 2019). The epidermal growth factor receptor (EGFR) plays a crucial part in the control of cell growth and is regarded as one of the most seriously evaluated tyrosine kinase's (TK) target inhibitors (El-Azab et al. 2010). Numerous TKs had a vital functions in cell propagation, division, metastasis and endurance, besides their uncontrolled triggering via processes such as point mutations leads to a substantial proportion of clinical cancers. EGFR is over expressed in numerous tumors, such as brain, lung, bladder, ovarian, colon, breast, head, and prostate tumors (Tiwari et al. 2015).
Components of the erbB class of EGFR-TKs, which comprise of erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4), are overexpressed in a substantial ratio of human tumors, and this is attributed to the miserable prognosis of the malady (Chandregowda et al. 2009). Hence, inhibitors of erbB1 and erbB2 were acknowledged as possible anticancer drugs (Hynes and Lane 2005).
Extermination of cancer cells without causing damage on other normal tissues or cells is the main purpose of anti-cancer drugs. However, the fact that some of these drugs usually destroys some other normal cells and the resistance to these drugs experienced by some patients during early period of treatment necessitates the global search for identifying new higher quality drugs that are safe for the prevention and remedy of cancer (Al-Suwaidan et al. 2016). Immediate recognition, understanding of the cause and pathway of this disorder, and improvement in remedy have played a pivotal part in curtailing breast cancer mortality rates over the past few years. Chemotherapy is still the central key to thorough therapy since it can exterminate tumor cells rapidly in the human system (Kaplan 2013).
In-silico approach of drug discovery have proven to accelerate the drug discovery process, as it lessen the time taken, resources and it enables the estimation of properties of new molecules such as toxicity and efficiency even before their synthesis. A mathematical relations that are able to establish a quantitative relationship between biological activities of a molecules and their molecular structures in form of linear equation is called Quantitative Structure-Activity Relationships (QSAR) (Abdullahi et al. 2021). Efficiency and safety of the drug to the system are the two major causes leading to drug failure. Therefore, it is compulsory to find potent molecules with better ADMET properties "drug-likeliness" (Lawal et al. 2021).
This research is mainly purposed in utilizing QSAR approach to compute the inhibitory activities of a series of quinazoline derivatives against MDA-MB231 breast cancer cell line, perform molecular docking studies to understand the nature of interaction between the compounds and the EGFR protein receptor, design new potent compounds based on their docking scores and examine their ADMET and drug likeness properties.

Data sets retrieval
A series of 23 quinazoline derivatives with inhibitory activities (IC 50 in µg/ml) against Triple Negative Breast cancer cell line MDA-MB231 are retrieved from Abuelizz et al. (2017). The inhibitory activities were linearized by taking their negative logarithm to base 10 as shown in Eq. 1.
Chemical structure of the quinazoline analogs as well as their respective inhibitive capacity at 50% concentration (pIC 50 ) are presented in Table 1.

Calculation of molecular descriptors
2D structures of the quinazoline analogs were sketched by utilizing Chemdraw version 16.0 and they were transformed to 3D format using Spartan 14 software. Molecular mechanics force field were employed to clean the 3D structures to eliminate all strain from the structure of (1) pIC 50 = −log 10 IC 50 × 10 −6 Keywords: Density function theory, Quantitative structure activity relationship, Triple negative breast cancer, Molecular docking, Pharmacokinetic studies  the molecule as well as guaranteeing a well-defined conformer relationship within the compounds (Viswanadhan et al. 1989). Density Functional Theory (DFT) quantum mechanical calculation was employed for the geometry optimization using B3LYP/631G * basis set. The optimized structures were saved in Spatial Document File (SDF) format and then exported to PADEL descriptor calculation software to compute the molecular descriptors (Amin and Gayen 2016).

Data set partitioning
The data set were partitioned into two separate set: Modeling set (training set) and external validation set (test set). The modeling set consist of eighteen (18) compounds while the external validation set is made up of five (5) compounds. Models are built using the modeling set while the predictive ability of the built model was ascertained using the external validation set (Tropsha et al. 2003). This splitting certifies that an analogous standard can be engaged to predict the activity of the test set. Kennard-Stone Algorithm was applied for dividing dataset into a modeling and test set (Kennard and Stone 1969).

QSAR model building and external validation
The most important aspect of QSAR studies is the designation and sampling of descriptors that offers an ultimate information in activity disparities and have minimal co-linearity. Hence, genetic function algorithm (GFA) progresses the model accurateness while selecting relevant molecular descriptors (Leardi 1996). Multi linear regression (MLR) was utilized on the model building set to express the mathematical relations between the depending variable A (pIC 50 ) and independent variable B (molecular descriptors). An exceptional feature of GFA algorithm is that it is able to generate multiple models rather than single model. Validation parameters that provides a guide in selecting the best QSAR model include correlation coefficient (R 2 ), adjusted R 2 (R 2 adj ), cross-validation coefficient (Q 2 cv ) and correlation coefficient of the external validation set (R 2 ext ), all are expressed in Eqs. (2, 3, 4 and 5) respectively.
where P is the number of independent variables in the model and N is the sample size. Y exp , Y pred , and Y mtraining are the experimental activity, the predicted activity, and the mean experimental activity of the compounds in the modeling set, respectively (Tropsha et al. 2003). The least recommended values for these parameters are shown in Table 2.

Y-randomization test
In order to assess the robustness of the model and to affirm that the model was not obtained by chance correlation Y-randomization was performed on the model building set data (Tropsha et al. 2003). A new QSAR model was generated using the descriptor matrix by shuffling the activity matrix randomly. A built QSAR model is robust and reliable only when it has low values of R 2 and Q 2 for numerous trials. Another validation parameter is the coefficient of determination for Y-randomization cR 2 p, and it should exceed 0.5 for passing this test as in Eq. 6 (2) cR 2 p is coefficient of determination for Y-randomization, R is the coefficient of determination for Y-randomization and Rr is average 'R' of random models.

Molecular docking studies
Ligand-Protein molecular docking studies was performed on all the quinazoline derivatives to study the nature of interactions between active pocket of the EGFR protein receptor and the ligands on HP laptop equipped with a dual-core Intel (R) PENTIUM (R) B940 CPU processor running at 2.0 GHz and 4.0 GB of RAM running on Windows 8 using Molegro Virtual Docker (MVD) software and Discovery studio.

Ligand preparation
The least energy optimized structures was saved in pdb file format prior to docking studies (Abdullahi et al. 2021).

Protein retrieval and Preparation
3D X-ray crystallized structure of the EGFR protein receptor (pdb id = 3ug2) was obtained from the protein data bank (https:// www. rcsb. org/), and was prepared on the MVD workspace by eliminating water molecules and co-crystallized ligand enclosed in the crystal structure. The amino acid residues with structural error were repaired/rebuilt. The Fully prepared protein structure was also save in pdb format prior to docking process.

Docking of the ligands and receptor using molegro virtual docker (MVD)
Due to its ability to produce a better and consistent results relative to other docking softwares, Molegro Virtual Docker software program was utilized for the docking study in this research. Before the start of the process, the prepared protein was exported from its folder to the MVD work space, cavities were detected and surface was created. The active pocket of the EGFR receptor was anticipated and was set inside a regulated sphere of X: 0.91 Y: 50.08 and Z: 22.54 with 15 Å radius respectively. The prepared ligands were imported into the MVD work space and docking process was executed using a grid resolution of 0.30 Å. The Root Mean Square Deviation (RMSD) threshold was set as 2.00 Å for the multiple clusters poses with 100.00 energy penalty values. The docking algorithm was set for a maximum of 1500 iteration with a maximum population size of 50. The docking simulation was run for a minimum of 50 times for the 10 poses, and the best poses were determined based on the MolDock score scoring function (Thomsen and Christensen 2006). Hydrogen bond, Hydrophobic, alkyl, pi-alkyl, Halo bonds and aryl intermolecular interactions were viewed with the aid of Discovery studio software.

ADMET and drug-likeness properties
pkCSM ((http:// structure. bioc.cam. ac.uk/pkcsm), and SwissADME (http:// www. swiss adme.ch/ index. php) are free and easily accessible online web sites that are utilized to explore the ADMET and medicinal properties of tiny molecules. The ADMET and Drug-resembleness properties of the compounds are obtained from these sites in the current research. At the pre-clinical phase of drug invention, the most crucial parameter is the Lipinski's rule of five (Abdullahi et al. 2021), and it states that any molecule that violates more than two (2) of the following criteria is not easily permeable or readily absorbed into the body system. The criteria are; MW ˂ 500, HBD ˂ 5, HBA ˂ 10, Log p ˂ 5 and PSA (PSA) ˂140 A 2 .

Structure based drug design
The design of drugs based on structures is also called the direct drug design, a very important, powerful and useful method of drug discovery. This includes the collection of information on the three-dimensional structure of the target receptor (protein) via approaches such as X-ray crystallography, NMR spectroscopy, or homology modeling, followed by the design of promising drug candidates based on binding and selective efficiencies for their target groups. The method involves several steps, such as retrieval and preparation of protein structure, preparation of ligand archives and manual design of new novel compounds (Batool et al. 2019).

Results
In this research work Genetic function algorithm was employed to generate the QSAR models due to its ability to produce a vast population of model instead of just a single model. Four models were generated from the model building set and the first one was chosen because of its statistical significance.

Discussion
The results of various statistical parameters of the selected model are shown in Table 1, therefore, the model satisfies the least required values for the evaluation of a robust QSAR model. Additionally, the selected model was utilized to estimate the inhibitive capacity of the external validation set and it was found to have passed the external validation test with R 2 ext = 0.655 (Table 2). The structures, experimental as well as predicted inhibitive activities of the compounds in this research work are placed in Table 1 respectively. A plot of experimental pIC 50 against the predicted pIC 50 of both the model building as well as the external validation set is shown in Fig. 1 (Ibrahim et al. 2018). Pearson's correlation matrix of the selected model indicates that descriptors are not correlated to each other, this illustrates that they are very good (Table 3).

Y-randomization test
Result of Y-randomization test is shown in Table 4 and the test is used to confirm that a model was not obtained by coincidental correlation. The coefficient of determination for Y-randomization cR 2 p is the most crucial parameter for this test and for a robust QSAR model its value must exceed 0.5. Its value in this research work is 0.74, this illustrates that the model is powerful enough and was not purely due to chance and has satisfied the minimal requirement for robustness.

Mean effect of the descriptors in the selected model
The mean effect designate the individual function and the influence of each descriptor in a model, and it is computed for each of the molecular descriptors using the below equation:  MF j denotes the mean effect for the indicated descriptor j, the coefficient of the descriptor j is denoted by β j , d ij is the value of the Target descriptor for each molecule and m population of descriptors in the model (Dimić et al. 2015).
The MF value offers essential information on the effect of each molecular descriptors in the picked model; the size and signals of these descriptors combined with their mean effects reveal their stability and path in inducing the activity of a molecule. The mean effect values are presented in Table 5. BCUTc-1l, MATS8c and SpMAD_Dzs were found to possess the most pronounced influence on the model performance due to their large and positive mean effect values. Their positive sign indicated that increase in their value increases the inhibitive activities of a compound against MDA-MB231 breast cancer cell line. The other descriptor, AATSC8c is negatively correlated with the inhibitive activities of the compounds against the breast cancer cell line, higher value of this descriptor will be responsible for hindering the potency of these compound.

Variance inflation factor (VIF)
The inter-correlation amongst molecular descriptors in a model is detected using their variation inflation factors (VIF), to check whether the descriptors are highly correlated with one another or not. computed VIF values less than 1 illustrates that there is no inter-correlation between the descriptors between 1 and 5, the model can be accepted; and if it is higher than 10, the model cannot be accepted. It can be calculated using the Eq. 8 below. In this research work VIF values for all the descriptors are less than 10, this demonstrates the fitness of the selected model and the descriptors were independent of one another (Table 3).   Fig. 3, the cut-off leverage is 0.833 hence, and only the external validation set compounds lies beyond the defined domain of applicability (leverage values > 0.833). These compounds affects the performance of the model but cannot be tagged as outliers since their standardized residual values lies within ± 3 region.

Molecular docking studies
Molecular docking studies is performed to have the knowledge on the nature of binding interactions and the amino acid residues that are accounted for inducing the biological activity of a molecule. In this research work docking simulation study was performed between all the studied quinazoline derivatives and the binding pocket of the EGFR protein receptor (pdb id = 3ug2) and the results are placed in Table 2. The reference drug (Gefitinib) was also redocked into the same binding pocket to revalidate the docking results. Eight compounds (6, 10, 13, 16, 17, 18, 19 and 20) were observed to have better docking score as well as experimental and predicted activities than Gefitinib as such they were tagged as potential hit compounds. Various types of Amino acid interactions between the potential hit compounds and the active site of the EGFR receptor are presented in Table 6.
Compound 6 is observed to have interacted with the binding site of the EGFR receptor via one (1) conventional Hydrogen bond, two (2) Carbon-Hydrogen bond, one (1) Pi-sulfur interaction and several Alkyl and Pi-Alkyl Interactions. The Carbonyl Oxygen of the quinazoline ring forms a conventional Hydrogen bond with MET793 at a distance 1.86 Å, and a Carbon-Hydrogen bond with LEU792 at a distance 2.46 Å. Other Carbon-Hydrogen bond is between the Hydrogen atom H8 and GLN791 amino acid residue at a distance 2.85 Å. The benzene ring intercalated in space and forms a π-Sulfur interaction with MET790 at a distance 3.46 Å. ALA743, LEU718, LEU792, CYS775, MET790, MET793, LEU844, VAL726 and LYS745 residues forms Alkyl interactions with the compound and ALA743, LEU844, LEU718, LYS745 and LEU788 amino acid residues forms π-Alkyl interactions. 2D and 3D binding nature of compound 6 in the binding pocket of the EGFR receptor is shown Fig. 4.
Compound 10 interacted with the binding pocket of the EGFR receptor through a single Conventional Hydrogen bond, double Carbon-Hydrogen bond, single electrostatic π-Cation Hydrogen bond, Hydrophobic π-Sigma, one π-Sulfur, and several Alkyl and π-Alkyl interactions. The quinazoline group carbonyl oxygen forms a conventional Hydrogen bond with MET793 at a bond distance 2.15 Å, and forms a Carbon-Hydrogen bond with LEU792 at a bond distance 2.79 Å, ALA743 forms the other Carbon-Hydrogen bond with the cyanide carbon at a bond distance 3.14 Å. The phenyl ring intercalated in space and forms a π-cation Hydrogen bond with LYS745 at a bond distance 3.10 Å. LYS745 also forms a single electrostatic π-Sigma with the benzene ring, CYS775 forms a π-Sulfur interaction with the benzene ring of the quinazoline scaffold at a distance 5.58 Å. CYS775, MET790, MET793 and LEU718 residues forms an Alkyl interactions while ALA743, MET790, LEU844, MET793 and LEU844 amino acid residues forms a π-Alkyl interactions with the compound. 2D and 3D binding mode of compound 10 in the binding site of the EGFR receptor is presented in Fig. 5 respectively. Compound 13 was observed to have interacted with the EGFR receptor via a single conventional Hydrogen bond, three (3) Carbon-Hydrogen bonds, a single π-sigma and π-Sulfur interaction and several hydrophobic alkyl and π-Alkyl interactions. The carbonyl oxygen of the quinazoline group forms a conventional and Carbon-Hydrogen bonds with MET793 and LEU792 at a bond distances 1.61 and 2.45 Å, other Carbon-Hydrogen bond interactions are observed between Methoxy Hydrogen atom and GLU762 at a distance 2.89 Å, Hydrogen atom H8 and GLN791 at a bond distance 2.84 Å. The phenyl ring of the quinazoline scaffold intercalated in space to form a π-sigma hydrophobic interaction with LEU718, a π-Sulfur interaction is observed between the other benzene ring and MET790. LEU718, CYS775, MET790, MET793 and LEU844 residues forms Alkyl interactions while LEU718, VAL726, ALA743, LEU844, LYS745 and LEU788 forms a Pi-Alkyl hydrophobic interactions. 2D and 3D binding mode of compound 13 in the binding site of the EGFR receptor (pdb id = 3ug2) is pictured in Fig. 6.
The binding interactions of compound 16 is through a single conventional and Carbon-Hydrogen  Figure 7 represent the 2D and 3D binding mode of  The binding mode of compound 17 is through single conventional Hydrogen bond, triple Carbon-Hydrogen bonds, single Pi-Sulfur interactions and many Alkyl as well as Pi-Alkyl Hydrophobic interactions. The quinazoline carbonyl oxygen interacted with MET793 to form a conventional Hydrogen bond at a distance 2.35 Å, and also forms a carbon-hydrogen bond when interacted with LEU792 at a distance 2.85 Å, the Nitro group oxygen forms another Carbon-Hydrogen bond with ASN842 at a bond distance 2.73 Å, Hydrogen atom of the methyl group that connects the quinazoline scaffold forms the other Carbon-Hydrogen bond with GLN791 at distance 2.69 Å. MET790 forms a Pi-Sulfur interaction, LEU718 and LEU792 forms an Alkyl interaction while LEU844, VAL726, ALA743, LEU718, CYS775, MET790 and MET793 forms a hydrophobic Pi-Alkyl interactions. 3D and 2D Binding interactions of compound 17 in the active site of the EGFR receptor is placed in Fig. 8.
The binding mode of compound 18 in the active site of the EGFR receptor is through a single conventional Hydrogen bond, an electrostatic π-Anion and π-alkyl interactions. Oxygen atom of the oxadiazole group forms a conventional Hydrogen bond with SER719 at a bond distance 2.88 Å, the quinazoline benzene ring moiety  intercalated in space and forms an electrostatic π-Anion interaction with ASP855. LEU844, VAL726, ALA743, LYS745 and MET790 amino acid residues forms Pi-Alkyl hydrophobic interactions. 2D and 3D binding mode of compound 18 in the binding site of the EGFR receptor (pdb id = 3ug2) are shown in Fig. 9. Compound 19 is bound to the active site of the EGFR receptor via two (2) conventional Hydrogen bonds, a single Pi-cation Hydrogen bond, a hydrophobic Pi-Sigma interaction, a Pi-sulfur and numerous Pi-Alkyl hydrophobic interactions. LYS745 and MET793 forms conventional Hydrogen bonds at bond distances 2.92 and 2.96 Å, LYS745 forms a Pi-Cation Hydrogen bond and Hydrophobic Pi-Sigma interactions at distances 3.33 and 2.57 Å, MET790 forms a Pi-sulfur interaction. VAL726, ALA743, LYS745, MET790, LEU788, LEU718 and LEU792amino acid residues formed Pi-Alkyl hydrophobic interactions.
2D and 3D binding mode of compound 21 in the active site of the EGFR receptor (pdb id = 3ug2) are placed in Fig. 10 respectively.
Binding mode of compound 20 is through two (2) conventional Hydrogen bonds, single Carbon-Hydrogen bond, single electrostatic Pi-anion, single Pi-Sulfur and hydrophobic Pi-Alkyl Interactions. Carbonyl Oxygen atoms of the quinazoline scaffold and Isoindoline-1,3-dione group forms conventional Hydrogen bonds with MET793 and LYS745 at distances 2.16 and 1.98 Å, Hydrogen atom of the methyl group that connects the quinazoline scaffold to the phenyl ring forms a Carbon-Hydrogen bond with GLN791 at distance 1.83 Å. ASP855 forms an electrostatic Pi-Anion interaction, MET790 forms a Pi-Sulfur Interaction, while VAL726, ALA743, LEU844, VAL726, CYS775, MET790 and MET793 forms a hydrophobic Alkyl interactions. 3D and 2D binding  interactions of compound 20 in the active site of the EGFR receptor is shown in Fig. 11 respectively. To validate the docking approach the reference drug, Gefitinib was also docked onto the binding pocket of the EGFR receptor and was observed to interact with the protein kinase via a single conventional Hydrogen bond, eight (8) Carbon-Hydrogen bond, single Pi-Sulfur    Figure 12 represent the 3D and 2D binding mode of Gefitinb in the active site of EGFR receptor.

Structure-based drug design
In this research work, all the quinazoline derivatives were docked on to the binding site of the EGFR (pdb id = 3ug2). Compound 19 (pred pIC 50 = 5.67, Residual = − 0.04 and MolDock score = − 123.238) was identified as the best compound since it has the best Moldock score and was excellently predicted by the model selected with least residual value and was within the defined applicability domain, hence, it is adopted as template for the design. Ten (10) novel compounds were designed by addition of various groups on the Meta, Para and Ortho positions of the isoindoline-1, 3-dione phenyl ring. The inhibitive activities of the designed compounds were predicted by the selected model and most of them possess an improved activity relative to the template compound. The structure, predicted activity and MolDock score of the designed compounds are presented in Table 7.

Molecular docking studies of the designed compounds
Molecular docking investigation was also performed for the designed compounds and the binding site of the EGFR receptor (pdb id = 3ug2) using Molegro Virtual Docker (MVD) software. The designed compounds were optimized to obtain the most stable and least energy conformer using DFT calculations utilizing B3LYP 631G* basis set and the optimized molecules were saved in pdb format. All the designed compounds displayed better docking scores compared to the Template and the reference drug (Gefitinib) utilized in the design. Types of amino acid interactions of the designed compounds and the active site of the EGFR receptor are presented in Table 8. The results of three (3) compounds with best docking scores are discussed in this research. Designed compound number three (3) has the best docking score (MolDock score = − 159.63) and it is found to interact with the EGFR receptor via three (3) Carbon-Hydrogen bonds, two (2) Alkyl and many Pi-Alkyl   Fig. 13. Designed compound 2 has the second best docking score (− 152.085) and it is found to have interacted with the EGFR receptor through three (3) conventional Hydrogen bonds, three (3) Carbon-Hydrogen bonds, single electrostatic Pi-Cation, Pi-Anion and Hydrophobic Pi-Sigma, two (2) Pi-Sulfur, single Alkyl and many Pi-Alkyl hydrophobic interactions. The Oxygen atom of the Isoindoline-1,3-dione forms a conventional Hydrogen bond with MET793 at a bond distance 1.66 Å, ASP855 forms another conventional Hydrogen bond with Hydrogen atom of the OH-group attached to the amino benzene group at a bond distance 1.87 Å, Carbonyl Oxygen of the quinazoline scaffold forms the other Conventional Hydrogen bond with CYS797 at a distance 2.26 Å. Similarly, Oxygen atom of the Isoindoline-1, 3-dione forms a Carbon-Hydrogen bond with LEU792 at a distance 2.77 Å, Methyl group Hydrogen atom attached to the Isoindoline-1,3-dione forms another Carbon-Hydrogen bond with MET793 at a distance 2.92 Å and the last one is between ASP800 and the Hydrogen atom of the methyl group that connects the phenyl ring to the main Quinazoline scaffold at a distance 2.87 Å. Additionally, the para-Hydroxy amino benzene intercalated in space to form an electrostatic Pi-Anion interaction with LYS745, ASP800 forms a Pi-Anion electrostatic interaction, GLY796 forms a Hydrophobic Pi-Sigma, MET790 and CYS797 forms a Pi-Sulfur interaction, LEU844 forms Alkyl and VAL726, ALA743 and LEU844 residues formed a hydrophobic Pi-Alkyl interactions. 3D and 2D binding pattern of designed compound 2 in the active site of the EGFR receptor (pdb id = 3ug2) is presented in Fig. 14.
Designed compound 6 also having a promising docking score (MolDock score = − 146.947) interacted with the active pocket of the EGFR receptor via two (2) conventional Hydrogen bonds, four (4) Carbon-Hydrogen bonds, two (2) Pi-Anion electrostatic interactions, and Pi-Alkyl hydrophobic interactions. LYS745 and ASP855 forms a conventional Hydrogen bonds with the Oxygen atoms of the Isoindoline-1,3-dione at a distances 1.54 Å and 2.68 Å, GLU762 forms a Carbon-Hydrogen bond with methyl group Hydrogen atoms attached directly to the Isoindoline group at distances 2.63 Å and 2.73 Å,  Fig. 15.

ADMET and pharmacokinetics studies of the designed compounds
The results of ADMET and Pharmacokinetics of the designed compounds are depicted in Tables 9 and 10 respectively. None of the compounds designed violate greater than two of the acceptable thresholds established by Lipinski's rule of five filters for tiny molecules. Accordingly, they were expected to be permeable across the cell membrane, easily absorbed, transported and diffused (Ibrahim et al. 2020). In addition, the designed

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The correspondents did not acknowledge competing of interest.