Discovery and Structure Optimization of a Series of Isatin Derivatives as Mycobacterium tuberculosis Chorismate Mutase Inhibitors

Abstract

In this study, the crystal structure of the Mycobacterium tuberculosis (MTB) enzyme chorismate mutase (CM) bound to transition state analogue (PDB: 2FP2) was used as a framework for virtual screening of the BITS-Pilani in-house database (2500 compounds) to identify new scaffold. We identified isatin as novel small molecule MTB CM inhibitors; further twenty-four isatin derivatives were synthesized and evaluated in vitro for their ability to inhibit MTB CM, and activity against M. tuberculosis as steps towards the derivation of structure-activity relationships (SAR) and lead optimization. Compound 3-(4-nitrobenzylidene)indolin-2-one, 24 emerged as the most promising lead with an IC50 of 1.01 ± 0.22 μm for purified CM and MIC of 23.5 μm for M. tuberculosis, with little or no cytotoxicity.

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

“…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.…”

“…In a similar fashion, the thiourea (11-17 and 22-25) and the sulphonamide derivatives (36-40) were assembled from the 1-(5-nitrothiazol-2-yl)piperidin-4-amine scaffold (3) by reacting with their corresponding isothiocyante and sulphonyl chloride respectively. 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).…”

“…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.…”

Synthesis and antimycobacterial activity evaluation of isatin-derived 3- [(4- aryl - 2- thiazolyl])hydrazone]-1h- indol- 2, 3- diones

“…Indoles, especially 1H-indole-2,3-dione (isatin) are the most prevalent heterocyclic scaffolds which have a broad spectra of medical applications such as anti-HIV, antiviral, anti-tumor, antifungal, antiangiogenic, anti-convulsant, and antiparkinsonian activity [6][7][8] . In particular, antituberculotic activity of various indole derivatives [9][10][11][12][13][14] and isatin derivatives [15][16][17][18][19][20][21][22] have attracted attention. The syn-thetic feasibility and extensive use of this scaffold have led to medicinal chemists to this ring which has also stemmed from the interest in the biological and pharmacological properties 23,24 .…”