Synthesis and Antitubercular Evaluation of Fluorinated 2-Cycloalkylimino Substituted 1,3-Benzothiazin-4-Ones

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

“…Against M. tuberculosis H 37 Rv, 2d inhibited growth at a concentration of 60 µM, whereas the other non-nitro BTZs studied did not show any antimycobacterial effect at the concentrations tested. In contrast to our results, Nosova et al reported a MIC of 0.7 µg mL −1 (2 µM) for 2a against M. tuberculosis H 37 Rv [21,22]. We assume that major differences in the assay protocols used are responsible for this observation.…”

“…A variety of methods for the synthesis of BTZs have been described in the literature [26]. The halogenated non-nitro BTZs studied in this work were synthesized from orthofluorobenzoic acids (1) as starting materials (Scheme 2), in analogy to the previously reported synthesis of 2a [21,22].…”

“…Treatment of 1 with thionyl chloride in toluene afforded the corresponding substituted benzoyl chlorides, which were reacted with ammonium thiocyanate in acetonitrile to yield the halogenated benzoyl isothiocyanates. Reaction with ethyl piperazine-1-carboxylate in acetonitrile gives the corresponding substituted thiourea intermediate products, which in general can be isolated in good yields [22]. In the work described here, the respective isothiocyanate and ethyl piperazine-1-carboxylate were treated in situ with triethylamine to obtain the halogenated BTZs 2 directly through an intramolecular heterocyclization reaction in a one-pot synthesis.…”

“…This is comparable with the conformations observed in 2a • H 2 O, 2e and molecule 1 in 2b. To date, the crystal structures of two fluorinated non-nitro BTZs have been reported, namely 6,7,8-trifluoro-2-(thiomorpholin-4yl)-1,3-benzothiazin-4-one (DOGXUV) [22] and 5-fluoro-2-(1-methyl-1H-pyrrol-2-yl)-1,3-benzothiazin-4-one (SOJ-GOQ) [40]. DOGXUV likewise exhibits a planar BTZ scaffold with the tethered thiomorpholin ring in a chair conformation.…”

“…Recently, Nosova et al published a series of fluorinated BTZs lacking a nitro group, for one of which, namely 5-fluoro-2-(4-ethoxycarbonylpiperazine-1-yl)-1,3-benzothiazin-4-one, a promising in vitro activity against M. tuberculosis H 37 Rv of 0.7 µg mL −1 (2 µM) was reported [21,22]. Motivated by these findings, we synthesized and structurally characterized the aforementioned most active compound described by Nosova et al and four related halogenated non-nitro BTZs and tested their in vitro activities against Mycobacterium aurum DSM 43999 and M. tuberculosis H 37 Rv.…”