Structure-Based Optimization of Pyridoxal 5′-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis

Abstract

The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure–activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium.

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

“…These enzymes are also essential for replication and persistence of M. tuberculosis in vivo . Among these, BioA, a key enzyme in biotin biosynthesis is a target for various scaffolds and these have been demonstrated to inhibit M. tuberculosis growth in vitro .…”

Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets

“…The pyrimidine imidazoles were introduced as a new class of antitubercular compounds based on a hit from a chemical library screen against M. bovis BCG. The chemical cluster that yielded hit 45 (Table 4) was confirmed cidal against Mtb (MIC 50 = 0.65 (Kumar et al, 2011;Awasthi et al, 2013) 3.1 EthR N-phenylphenoxy acetamides N/D (Flipo et al, 2012) 4.1 LepB Arylhydrazones N/D (Bonnett et al, 2016) 5.1 CysM Diphenyl ureas N/D (Brunner et al, 2016) 6.1 BioA Benzoyl piperazines N/D (Park et al, 2015;Liu et al, 2017) 7.1 IMPDH Indazole sulfonamides No (Park et al, 2017) 7.2 Benzoxazoles N/D (Chacko et al, 2018)…”

Novel piperazine–chalcone hybrids and related pyrazoline analogues targeting VEGFR-2 kinase; design, synthesis, molecular docking studies, and anticancer evaluation

“…As illustrated in Table 1, compound Vf bearing 3-fluoropyridine moiety showed weak anti-proliferative activity against non-small cell lung cancer HOP-92, leukaemia K-562, colon cancer HT29, leukaemia SR, and breast cancer MCF7 cancer cell lines, with cell growth promotion (82.34%, 85.84%, 86.42%, 92.99%, 99.38%; cell growth inhibition: 17.66%, 14.16%, 13.85%, 7.01%, and 0.62%, respectively). It also showed moderate activity against leukaemia HL- 60 HL-60(TB), non-small cell lung cancer HOP-92, leukaemia CCRF-CEM, leukaemia SR, and breast cancer MCF7 with percent growth inhibition of 39.17%, 41.59%, 41.82%, 44.28%, and 48.28%, respectively, compared to that of compound Vf (20.72%, 17.66%, 21.84%, 7.01%, and 0.62%, respectively). In addition, compound Vd, showed good to excellent activity against colon cancer HCT-116, colon cancer HT29, and leukaemia K-562 with percent growth inhibition of 57.92%, 69.56%, and 83.45%, respectively.…”