Preliminary Structure–Activity Relationships and Biological Evaluation of Novel Antitubercular Indolecarboxamide Derivatives Against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains

Abstract

Tuberculosis (TB) remains one of the leading causes of mortality and morbidity worldwide, with approximately one-third of the world's population infected with latent TB. This is further aggravated by HIV coinfection and the emergence of multidrug- and extensively drug-resistant (MDR and XDR, respectively) TB; hence the quest for highly effective antitubercular drugs with novel modes of action is imperative. We report herein the discovery of an indole-2-carboxamide analogue, 3, as a highly potent antitubercular agent, and the subsequent chemical modifications aimed at establishing a preliminary body of structure-activity relationships (SARs). These efforts led to the identification of three molecules (12-14) possessing an exceptional activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis , with minimum inhibitory concentration (MIC) values lower than those of the most prominent antitubercular agents currently in use. These compounds were also devoid of apparent toxicity to Vero cells. Importantly, compound 12 was found to be active against the tested XDR-TB strains and orally active in the serum inhibition titration assay.

Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis

“…A number of structurally diverse hydrophobic inhibitors have been reported in the last 2 years to target the essential TMM transporter MmpL3 (7,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)21). Various explanations have been advanced for this apparent bias, including the fact that MmpL3 may represent a particularly vulnerable and druggable target and/or one in which spontaneous resistance-conferring mutations may be easier to achieve (12).…”

“…Surprisingly, in the last 2 years, the whole-cell-based screening of compound libraries against M. tuberculosis in culture coupled to the whole-genome sequencing of spontaneous resistant mutants identified a variety of pharmacophores that apparently shared the same mode of action as SQ109. These inhibitors include the 1,5-diarylpyrrole derivative BM212 and analogs (10,11), the benzimidazole C215 (12), tetrahydropyrazolo [1,5-a]pyrimidine-3-carboxamides (THPPs) (13,14), N-benzyl-6=,7=-dihydrospiro[piperidine-4,4=-thieno [3,2-c]pyrans (13), indolecarboxamides (15)(16)(17)(18), and adamantyl ureas (AUs) (19) (Fig. 1).…”

Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

“…In addition, compound 61 was found to be highly active against two XDR TB strains with MIC values of 0.0067 0.026 μM. 28 The PK studies of compound 61 at 100 mg/kg oral dose to mouse exhibited C max of 1.6 μM and AUC of 12.4 μM h, well above the MIC. Compound 61 showed dose dependent anti TB activity when orally administered to Mtb infected mice at 33, 100, and 300 mg/kg for 4 weeks after 2 weeks infection, however the ef cacy of 61 was weaker than that of isoniazid (1) at 10 mg/kg (61: 0.38 0.55 vs. isoniazid (1): 2.7 log CFU reduction).…”

“…In the case of BTZ043 (27), the resulting nitroso species covalently binds to a cysteine residue in the active site of DprE1, thereby irreversibly blocking the enzymatic catalyzed epimerization reaction. 16 During the pre clinical development of BTZ043 (27), a follow up medicinal chemistry program resulted in the identi cation of PBTZ169 (28) with no chiral center, providing easier synthesis than BZT043 (27). 17 PBTZ169 (28) exhibits comparable in vitro and in vivo anti TB activities to BZT043 (27), and is water soluble in salt form.…”

“…17 PBTZ169 (28) exhibits comparable in vitro and in vivo anti TB activities to BZT043 (27), and is water soluble in salt form. PBTZ169 (28) is now under evaluation of pre clinical toxicology pro le.…”