Synthesis of highly potent novel anti-tubercular isoniazid analogues with preliminary pharmacokinetic evaluation.
Ramani AV, Monika A, Indira VL, Karyavardhi G, Venkatesh J, Jeankumar VU, Manjashetty TH, Yogeeswari P, Sriram D.
Thirty two novel isoniazid analogues were prepared by one-pot three component condensations of isoniazid (INH), 3-mercaptopropionic acid and various aryl/heteroaryl aldehydes. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and cytotoxicity. Among the compounds, compound N-(2-(4-(benzyloxy) phenyl)-4-oxo-1,3-thiazinan-3-yl) isonicotinamide (17) inhibited MTB with MIC of 0.12 μM and was three times more potent than INH. The main pharmacokinetic parameters after intravenous administration (10 mg/kg body weight) in male Wistar rats viz. t(½), K(el), mean plasma clearance and mean volume of distribution were found to be 1.14±0.20 h, 0.62±0.10 h(-1), 22.48±0.16 mL/kg/min and 1.99±0.49 L, respectively. The systemic absorption was slow after oral administration (50 mg/kg body weight). The peak plasma concentration was found to be 1.31±0.06 μg/mL attained in 3 h. The bioavailability was found to be 16.7%.