Structural elucidation of the antitubercular benzothiazinone BTZ043: A combined X-ray, variable temperature NMR and DFT study

Abstract

A structural study of (S)-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-8-nitro-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one (BTZ043), a promising antitubercular drug candidate, is reported. The chiral compound crystallizes in the triclinic system (space group P1) with two molecules in the asymmetric unit (Z’ = 2), which are related by pseudo inversion symmetry. The two crystallographically distinct molecules represent diastereomeric conformers, which can be transformed to one another by an approximate 180° rotation about the C2BTZ−Npiperidine bond connecting the (S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]decane side chain to C2 of the benzothiazinone (BTZ) scaffold. Variable temperature 13C NMR measurements of BTZ043 in CDCl3 in the range 248-333 K indicate a rotational barrier of Ea = 17.1 ± 1 kcal mol−1 and ΔGǂ = 14.6 ± 1 kcal mol−1. DFT calculations reveal two barriers to rotation about the C2BTZ−Npiperidine bond, one larger than the other by 4.1 kcal mol−1.