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

Abstract

Abstract8-Nitro-1,3-benzothiazin-4-ones (BTZs), with BTZ043 and PBTZ169 as the most advanced compounds, represent a new class of potent antitubercular agents, which irreversibly inhibit decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1), an enzyme crucial for cell wall synthesis in the pathogen Mycobacterium tuberculosis. Synthesis, structural characterization and in vitro testing against Mycobacterium aurum DSM 43999 and M. tuberculosis H37Rv of halogenated 2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-ones lacking a nitro group are reported. X-ray crystallography reveals that the structure of the BTZ scaffold can significantly deviate from planarity. In contrast to recent reports, the results of the present study indicate that further investigation of halogenated non-nitro BTZs for antitubercular activity is less than a promising approach.

Recent Advances of DprE1 Inhibitors against Mycobacterium tuberculosis: Computational Analysis of Physicochemical and ADMET Properties

“…To investigate the molecular diversity and ADMET properties of the DprE1 inhibitors disclosed in this review, we collected a data set of a total of 1519 structurally diverse molecules by reviewing the literature from the year 2009 to April 2022. − ,− …”

“…Numerous scaffolds acting noncovalently also have been investigated for their activity against Mtb and are depicted in Table . These inhibitors include non-nitro BTZ analogues (NC BTZ), − benzothiazoles (BTO), , 1,2,3-triazole-2-mercaptobenzothiazoles (2-S-BTO), 1,4-azaindoles (AZA), − benzimidazoles (BI), pyrazolopyridones (PP), 4-aminoquinolone piperidine amides (4-AQ), 2-carboxyquinoxaline derivatives (2-CQ), pyrrolothiadiazoles (PTD), , morpholine-pyrimidines (MP), N -alkyl-5-hydroxypyrimidinone carboxamides (NAHPC), , hydantoins (HYD), , benzodioxanes (BD), 3,4-dihydrocarbostyril derivatives (CD), − thiophene-arylamide compounds (TPA), N -(4-hydroxy-3-mercaptonaphthalenyl) sulfonamides (NHMS), and avermectins (AVMT) …”

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

“…Notably, C2 modifications of BTZ like 4‐carbonyl piperazine, [ 16–18 ] 4‐sulfonyl piperazine, [ 19 ] N ‐(amino) piperazine, [ 20,21 ] 4‐methylene piperidine, [ 22 ] 4‐oxy piperidine, [ 23 ] spirocyclic and bicyclic, [ 24–26 ] 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

“…X-ray crystallography also revealed the BTZ core can be virtually planar or significantly non-planar in several halogenated non-nitro BTZs. 63 Of these, the ethylcarboxy derivative of 5-fluoro-2-(piperazin-1-yl)-4 H -benzo[ e ][1,3]-thiazin-4-one 23 , crystallizes as a monohydrate, as shown in Fig. 12.…”

“…61 Motivated by these results, we (re)investigated in vitro activity of this compound and several halogenated non-nitro BTZs, but using a different assay protocol we could not find potent inhibitory effects. 63…”