Identification of benzothiazinones containing 2-benzyl-2,7-diazaspiro[3.5]nonane moieties as new antitubercular agents

Development of Predictive Classification Models for Whole Cell Antimycobacterial Activity of Benzothiazinones

“…Table shows the results for representative compounds (see Table S1 for the complete set of compounds). The observed activity spanned 5 orders of magnitude [minimal inhibitory concentration (MIC) values, ranging from 126 μM to 2.74 nM, for the lowest and most potent compounds, respectively], demonstrating the strong influence of the side chain (ring C; Figure A) on the antimycobacterial activity, as previously observed. ,,,− Figure A shows the density distribution of the antimycobacterial activity of the compounds according to their respective groups. A markedly higher density of potent substances (high pMIC) was observed within the groups of compounds bearing piperidine (group 1: 5–19 ; median MIC: 52 nM) and piperazine moieties (group 3: 27–61 ; median MIC: 62 nM).…”

“…The structure–activity relationships (SARs) for BTZs have been explored by different research groups. As a result, apart from the nitro group, the trifluoromethyl moiety has shown to be essential for bioactivity. ,,,, From the perspective of the ligand–target interactions, the most bearable changes on 1 could be carried out on the side chain (2-methyl-1,4-dioxa-8-azaspiro[4.5]­decane; Figure A), which has therefore been the focus of most SAR reports. ,,,− Despite the pronounced solvent exposure of this part of the molecule when bound to DprE1 (Figure B), the side chain seems to be extremely relevant for defining activity, probably providing a delicate adjustment of lipophilicity, polarity, and other prerequisites for mycobacterial cell permeability. For instance, high Log P values have been recognized to be typically necessary to enable passive diffusion through the mycolic acid layer (natural barrier in Mtb ). , …”

Tuberculosis Drug Discovery: Challenges and New Horizons

“…A new study by these investigators pinpointed compound 39 (Figure ) as an improved lead . This molecule provided similar MIC 90 potency against Mtb H37Rv (<0.028 μM), was noncytotoxic to Vero cells (CC 50 > 112 μM), and was well tolerated by mice at 2 g/kg.…”

Synthesis and evaluation of triazole congeners of nitro-benzothiazinones potentially active against drug resistant Mycobacterium tuberculosis demonstrating bactericidal efficacy

“…Since the 6-trifluoromethyl-8-nitrobenzothiazinone heterocycle is indispensable to the potency of BTZ, quite a number of alterations have been directed at the more tolerant C-2 position of the BTZ core. Consequently, replacement of the piperazine of PBTZ with various linkers like piperidine, 16 spiro-heterocycles bearing a 2-benzyl-2,7-diazaspiro[3.5]nonane moiety, 17,18 and different spiro and bicyclic motifs 19 has been reported to result in a better PK profile without significantly modulating potency with respect to MCZ. Apart from these classical BTZ containing hetero-alicyclic C-2 modified moieties, 2-amino substituted BTZ I has been found to demonstrate potent inhibition.…”