SAR Studies on Trisubstituted Benzimidazoles as Inhibitors of Mtb FtsZ for the Development of Novel Antitubercular Agents

Abstract

FtsZ, an essential protein for bacterial cell division, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of two lead 2,5,6-trisubstituted benzimidazoles, 1 and 2, targeting Mtb-FtsZ in our previous study, an extensive SAR study for optimization of these lead compounds was performed through systematic modification of the 5 and 6 positions. This study has successfully led to the discovery of a highly potent advanced lead 5f (MIC 0.06 µg/mL) and several other compounds with comparable potencies. These advanced lead compounds possess a dimethylamino group at the 6 position. The functional groups at the 5 position exhibit substantial effects on the antibacterial activity as well. In vitro experiments such as the FtsZ polymerization inhibitory assay and TEM analysis of Mtb-FtsZ treated with 5f and others indicate that Mtb-FtsZ is the molecular target for their antibacterial activity.

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

“…Among these compounds, 46 and 47 ( Figure 7) were reported to effectively inhibit clinical isolates of M. tuberculosis possessing different resistance profiles, with MIC values ranged from 0.06 to 0.16 μg mL −1 . Moreover, light scattering assay and TEM analyses indicated that these compounds obviously inhibited polymerization of M. tuberculosis FtsZ [119]. From all these results, it was suggested that the antimicrobial activity of these trisubstituted benzimidazoles can be attributed to their interaction with M. tuberculosis FtsZ.…”

Identification of Agents Targeting Ftsz Assembly

“…In separate studies [88,90], SB-P3G2 10b, SB-P8B2 10a, SB-P17G-C2 10c, SB-P17G-A20 10d and SB-P20G3 10e (Figure 4) have been tested for their efficacy to inhibit the growth the clinical isolates of drugsensitive and drug-resistant strains of M. tuberculosis. These compounds display MIC values ranging from 0.06 to 1.25 μg/ml and have been found to inhibit the polymerization of FtsZ In vitro.…”

Design, synthesis and evaluation of novel 2,5,6-trisubstituted benzimidazoles targeting FtsZ as antitubercular agents

“…As both of these compounds share a common benzimidazole moiety, we chose benzimidazole as the scaffold for development of novel anti-TB agents. In our previous work, 16, 17 based on rational drug design, libraries of 2,5,6- and 2,5,7-trisubstituted benzimidazoles were synthesized and evaluated for anti-TB activities. A large number of compounds were identified with MICs in the range of 0.38–6.2 strains μg/mL against drug sensitive as well as drug resistant Mtb (Fig.…”

“…17, 18 Building upon three representative compounds bearing alkyl carbamate or benzamide at the 5-position, we planned to expand our novel trisubstituted benzimidazole libraries with a substitution pattern different from the previous series for high throughput (HTP) screening. 19 [ Note : In the 6-amino series, we have very recently found that the 6-dimethylamino series exhibit excellent activities up to the MIC value of 0.06 μg/mL.…”

“…19 [ Note : In the 6-amino series, we have very recently found that the 6-dimethylamino series exhibit excellent activities up to the MIC value of 0.06 μg/mL. 17 ]…”