Gyrase ATPase Domain as an Antitubercular Drug Discovery Platform: Structure‐Based Design and Lead Optimization of Nitrothiazolyl Carboxamide Analogues

Abstract

In this study, we explored the pharmaceutically underexploited mycobacterial gyrase ATPase (GyrB) domain as a template for a structure-based virtual screening of our in-house (BITS Pilani) compound collection to discover new inhibitors targeting Mycobacterium tuberculosis (M.tb.) The hit identified was further customized by using a combination of molecular docking and medicinal chemistry strategies to obtain an optimized analogue displaying considerable in vitro enzyme efficacy and bactericidal properties against the M.tb. H37 Rv strain. The binding affinity of the ligand toward the GyrB domain was reascertained by differential scanning fluorimetry experiments. Further evaluation of the hERG toxicity (a major limitation among the previously reported N-linked aminopiperidine analogues) indicated these molecules to be completely devoid of cardiotoxicity, a significant achievement within this class.

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).…”

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

“…To provide a structural basis for further inhibitor improvement, compound 12 was subjected to molecular docking calculations using the crystal structure of gyrB ATPase domain of Mycobacterium smegmatis retrieved from Protein Data Bank (PDB ID -4B6C) 22 as template; utilizing a protocol detailed in the experimental section. The compound exhibited good interaction profile in docking studies retaining critical polar and non polar interaction comparable to that of (3,4-dichloro-5-methyl-N-[4-(5-nitro-1,3-thiazol-2-yl)cyclohexyl]-1H-pyrrole-2-carboxamide, a potent gyrB inhibitor [gyrB IC 50 = 0.49 µM], identified from our earlier study 28 with an RMSD of less than 0.5 Å as shown in Figure 2 suggesting the suitability of the identified hit for further structure activity explorations.…”

“…All these modification resulted in very potent molecules as shown in Tables 2, 3 and 4. The N-benzyl amino (26)(27)(28)(29)(30), carboxamide (31)(32)(33)(34)(35) was well accommodated as the right hand core than their corresponding sulphonamide analogues (36- A structural insight into the interaction profile of the most potent compound inhibitor from the study compound 27 (Figure 4) showed the molecule to be involved in polar contact with Asn52, a crucial residue of gyrB. Additionally, a cation-π interaction was also observed between the amino group of Arg82 and thiazole of compound.…”

“…The amide derivatives (31)(32)(33)(34)(35) were developed by coupling the scaffold derivative (3) with the respective acid using propyl phosphonic anhydride as the coupling agent. Finally reductive amination of 1-(5-nitrothiazol-2-yl)piperidin-4-amine with desired aldehydes gave the designed amino derivatives (26)(27)(28)(29). The Chan-Lam methodology [29][30][31] was successful in achieving the N-phenyl analogue (30).…”

“…Later, various N-benzyl/phenyl amino (26)(27)(28)(29)(30), carboxamide (31)(32)(33)(34)(35) and sulphonamide derivatives (36)(37)(38)(39)(40) were also explored as the right hand partner to have a clear profiling of the structure activity relationship. All these modification resulted in very potent molecules as shown in Tables 2, 3 and 4.…”