Molecular Insight into the Discrepancy of Antitubercular Activity between 8‐Nitro and 8‐Cyano Benzothiazinones

Abstract

Benzothiazinones with 8-NO 2 group is a novel class of compounds with potent antitubercular activity, especially BTZ043 and PBTZ169, which covalently inhibit DprE1. 8-CN benzothiazinones is reported as another type of benzothiazinones with potent antitubercular activity. Taking this as the starting point, a series of 8-CN benzothiazinones are synthesized and evaluated for their antitubercular activity. To better understand the antitubercular activity of this series of benzothiazinones, the difference between the molecular structures of CN01 and PBTZ169 in crystal are analyzed. CN01 and PBTZ169 show completely different conformations of the piperazine ring. Density functional theory analysis (DFT) and molecular dynamics (MD) simulation are performed to provide more details to explain the different antitubercular activity. All the analysis based on crystallography, quantum chemistry, and molecular modeling lay a foundation for the subsequent structural optimization of 8-CN benzothiazinones.

Bioevaluation of quinoline‐4‐carbonyl derivatives of piperazinyl‐benzothiazinones as promising antimycobacterial agents

“…Notably, C2 modifications of BTZ like 4-carbonyl piperazine, [16][17][18] 4-sulfonyl piperazine, [19] N-(amino) piperazine, [20,21] 4-methylene piperidine, [22] 4-oxy piperidine, [23] spirocyclic and bicyclic, [24][25][26] fused ring and amino-substituted derivatives, [27,28] cyclic ketoxime moiety, [29] oximido, [30] and C6 methane sulfonyl analogs [31] has produced BTZs with improved PK attributes. In addition, several non-nitro BTZs including C8 triazole, [32] nitrile, [33,34] various covalent warheads, [35] halogenated BTZ, [36,37] and piperazinyl urea/thioureas [38] were reported displaying good to moderate potency that further reinforced the covalent mechanistic activity of BTZs along with corroborating the invaluable nature of C8 nitro group. Although essential for better penetration and potency, the aliphatic side chain contributes to the low aqueous solubility of BTZs that subsequently leads to poor bioavailability.…”

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

“…31) nearly at the same time. 60,92,93 MICs of 0.03 93 and 0.13 60,92 μM against M. tuberculosis were reported. Zhang et al Liu et al were able to demonstrate covalent adduct formation with DprE1 by mass spectrometry for PBTZ169 with the 8-nitro group replaced by electrophilic acrylate containing moieties but not for 48 .…”

“…93 Based on in silico results, Zhang et al likewise suggested that 48 non-covalently binds to DprE1. 60 In another publication, however, they hypothesized that 48 maintains activity through formation of a covalent thioimidate linkage with Cys387 in analogy to the semimercaptal formation of 8-nitro-BTZs, albeit without providing experimental evidence. 92 Interestingly, Nosova et al reported promising in vitro activity (MIC = 2 μM) for the fluorinated non-nitro BTZ 23 (Fig.…”

Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones

“…In March 2021, only four small molecule structures of BTZs were available in the Cambridge Structural Database (CSD) [37], as revealed by a WebCSD search [38]. The crystal structure of PBTZ169 (CSD refcode: LOPXAS) was reported by Zhang and Aldrich [39] and that of its 8-CN analogue (WALHAW) very recently by Zhang et al [18]. A virtually planar BTZ scaffold and a chair conformation of the piperazine ring are encountered in both structures.…”

“…Thus, efforts have been made to develop antitubercular BTZs in which the nitro group at C-8 of the BTZ scaffold has been replaced by e.g. a pyrrole [16], an azide [17] or a cyano group [18][19][20].…”