Thiazolopyridone ureas as DNA gyrase B inhibitors: optimization of antitubercular activity and efficacy.
Kale RR, Kale MG, Waterson D, Raichurkar A, Hameed SP, Manjunatha MR, Kishore Reddy BK, Malolanarasimhan K, Shinde V, Koushik K, Jena LK, Menasinakai S, Humnabadkar V, Madhavapeddi P, Basavarajappa H, Sharma S, Nandishaiah R, Mahesh Kumar KN, Ganguly S, Ahuja V, Gaonkar S, Naveen Kumar CN, Ogg D, Boriack-Sjodin PA, Sambandamurthy VK, de Sousa SM, Ghorpade SR.
Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 μM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.