Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure–Activity Relationship, Metabolism, and Biology Triaging

Abstract

Screening of a library of small polar molecules against Mycobacterium tuberculosis (Mtb) led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure–activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated in vivo for pharmacokinetic properties. Mtb-mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre

“…In another whole-cell screening campaign, two potent hit series (MIC of <0.5 μM), the pyrrolo[3,4- c ]pyridine-1,3(2 H )-diones exemplified by compound 12 ( 30 ) and benzoheterocyclic oxime carbamates represented by compound 13 , 31 were identified ( Figure 4 ). The oxime carbamate containing compounds displayed potent activity (MIC < 0.08–0.31 μM) against drug-susceptible clinical Mtb isolates.…”

“…During SAR, cytotoxicity, solubility, and ADME/PK profiling, it was discovered that while the parent carbamates maintained activity, the free oximes were inactive ( Figure 5 ). 31 To investigate this, we hypothesized that the carbamate group masks the oxime in the compounds to improve permeation across the Mtb cell wall. Once the compounds are in the bacilli, these can easily be enzymatically cleaved via esterase activity.…”

“… Proposed prodrug-based activity of carbamate-functionalized oxime compounds. 31 Reproduced from ref ( 31 ). Copyright 2021 American Chemical Society.…”

Tandem Repeat of a Short Human Chemerin-Derived Peptide and Its Nontoxic d-Lysine-Containing Enantiomer Display Broad-Spectrum Antimicrobial and Antitubercular Activities

“…The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01352. HPLC profiles of the peptides; MALDI-TOF mass spectra of the peptides; RP-HPLC chromatograms of Chem-KVL and Chem-8dK after incubation with the 10% human serum at different time intervals, and MALDI-TOF mass spectra of Chem-KVL and Chem-8dK peptides after incubation with 10% human serum for 15…”

“…Streptomycin was introduced as the first TB drug in 1947, but soon, it became ineffective due to the development of resistance in mycobacteria against this antibiotic (WHO Global tuberculosis report, Geneva, 2016; WHO treatment of tuberculosis guidelines, World Health Organization, Geneva, 2010) . Efforts are being made for the identification of small organic molecules as potential new antituberculosis drugs. − Researchers have also attempted to screen some antitubercular peptides for the treatment of tuberculosis with different therapeutic strategies, for example, as a new antitubercular drug and in combination with an already known drug with synergistic effect. However, not many AMPs show activity against mycobacteria …”