Thiazolopyridine Ureas as Novel Antitubercular Agents Acting through Inhibition of DNA Gyrase B

Abstract

A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 μM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

“…The catalytic subunits (GyrA/ParC) are clinically validated drug targets of the fluoroquinolones, such as moxifloxacin (MXF) (2), while the ATPase subunits (GyrB/ParE) have not been as extensively exploited and may present a new option for treating DR strains of M. tuberculosis (3). Furthermore, several different chemical classes have been described as inhibitors of gyrase B with potent activity against DR bacteria, including M. tuberculosis (4)(5)(6)(7)(8)(9)(10).…”

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

“…Além disso, a atividade biológica de diversos heterociclicos já foram descritos como sendo ativos contra a subunidade GyrB, como por exemplo derivados de cumarina, benzimidazol uréia, pirazol, indazol e indolinona. 110,111 Utilizando inibidores de GyrB identificados previamente, foram sintetizados 26 derivados do etil 5-(piperazina-1-il) benzofurano-2--carboxilato, que foram avaliados contra cepas de MTB H 37 Rv. O composto 41 se apresentou como o mais promissor da série, exibindo uma CIM 90 de 9.18 μmol L -1 .…”

“…Estudos in vivo utilizando camundongos com infecção aguda de tuberculose revelaram ação bactericida deste composto em dois diferentes regimes de administração oral (300 mg kg -1 uma vez ao dia ou 150 mg kg -1 duas vezes ao dia) durante 10 dias. 111 Esses resultados sugerem a importância da subunidade GyrB como potencial alvo terapêutico a ser explorado no desenvolvimento de fármacos antituberculose.…”

Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: Hit to lead optimization of a novel class of thiazole inhibitors

“…Inhibitor of gyrB subunit competitively inhibits the ATPase activity conferred by the DNA gyrB subunit and thereby abolishes the energydependent reactions catalyzed by DNA gyrase . [15][16][17][18][19][20] In the present study, we explore a new class of DNA gyrase inhibitor derived from the medium throughput screening (MTS) of BITS-Pilani in house chemical library using the relatively underexploited gyrase ATPase domain as the template. The hit obtained was further customized using medicinal chemistry strategies to obtain a lead molecule displaying considerable in vitro enzyme efficacy and anti-mycobacterial potency against MTB H3Rv strain.…”