A Trisubstituted Benzimidazole Cell Division Inhibitor with Efficacy against Mycobacterium tuberculosis

Abstract

Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73±0.24 Log10 CFU and 2.68±Log10 CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy.

Recent advances in the discovery and development of antibacterial agents targeting the cell-division protein FtsZ

“…94 SB-P3G2 and SB-P8B2 were found to have modest activity against non-replicating M. tuberculosis cells grown under low oxygen conditions, which suggested that this series of compounds might have efficacy against latent TB infections. 95 In the in vivo efficacy study of SB-P3G2 and SB-P17G-A20 using an acute TB infection model in GKO mice showed SB-P3G2 reduced the bacterial load of M. tuberculosis H37Rv by 0.7 ± 0.17 log 10 CFU in the lungs and 0.41 ± 0.36 log 10 CFU in spleen, 95 while SB-P17G-A20 reduced the bacterial load by 1.73 ± 0.24 log 10 CFU and 2.68 ± 0.48 log 10 CFU in lungs and spleen, respectively.…”

Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis

“…To assess the performance of the SMEDDS formulation on the delivery and efficacy of diphenyl ether lead candidates, and co-treatment, SB-PT070 and SB-PT091 were tested in combination with RIF using SMEDDS in our rapid murine Mtb infection model of dissemination described previously 18, 19 In this rapid model to assess drug efficacy, bacteria a delivered to the lungs and treatment is initiated day 5 post infection before the bacteria disseminate to the spleen. Since we have found that dissemination is important to the pathogenesis of tuberculosis as well as other respiratory pathogens, drugs and drug candidates that control dissemination from the infection sight of the lungs to secondary locations such as the spleen are more efficacious at controlling prolonged infection and relapse 33-37 .…”

“…18, 19 In this rapid model animals are infected using the low dose aerosol infection followed by treatment for 10 consecutive days starting 5 days post infection. Compounds were solubilized in specified formulations and delivered at the given route and dose.…”

“…19 The fractional inhibitory concentrations (FICs) were calculated to determine synergy in the drug combinations as described. 2021 FIC is defined as the MIC of a drug in combination divided by the MIC of that drug alone.…”

Identification of Agents Targeting Ftsz Assembly

“…A number of these compounds have been found to inhibit the growth of M. tuberculosis H37Rv with an MIC value ≤5 μg/ml, with nine compounds having MIC values between 0.5 and 6.1 μg/ml. Recently, a series of 2-cyclohexyl-5-acylamino-6-N,N-dimethylaminobenzimidazoles derivatives has been synthesized and two, SB-P17G-A20 10d and SB-P17G-C2 10c (Figure 4), have been found to be most effective against clinically pathogenic strains of M. tuberculosis, with MIC values 0.16 and 0.06 μg/ml, respectively [89]. SB-P17G-C2 10c has been found to be highly labile in the presence of mouse and human liver microsomes in comparison to SB-P17G-A20 10d, indicating that it has more acceptable physicochemical properties.…”