Macozinone: revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb), the principal etiological agent of tuberculosis (TB), infects over one-quarter of humanity and is now the leading cause of infectious disease mortality by a single pathogen. Macozinone {2-[4-(cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, C20H23F3N4O3S} is a promising new drug for treating drug-sensitive and drug-resistant TB that has successfully completed phase I clinical trials. We report the complete spectroscopic and structural characterization by 1H NMR, 13C NMR, HRMS, IR, and X-ray crystallography. The cyclohexyl moiety is observed to be nearly perpendicular to the core formed by the 1,3-benzothiazin-4-one and piperazine groups. The central piperazine ring adopts a slightly distorted chair conformation caused by sp 2-hybridization of the nitro N atom, which donates into the electron-deficient 1,3-benzothiazin-4-one group.

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

“…Seven 8-CN benzothiazinones were synthesized and characterized by 1 HNMR, 13 CNMR and HRMS. Due to the unexpected antitubercular activity (65-fold discrepancy), we characterized CN01 by X-ray crystallography and compared the crystal of CN01 to that of PBTZ169.…”

“…In order to investigate the antitubercular activity difference between PBTZ169 and CN01, CN01 was crystallized and characterized by X‐ray diffraction (Table S1, Figure 1). Compared to the crystal structure of PBTZ169, [13] the key feature of CN01 was the planar 1,3‐benzothiazin‐4‐one scaffold. Unexpectedly, the dihedral angle between the 1,3‐benzothiazine‐4‐one and the least‐square plane of the appended piperazine is different from PBTZ169 (Table S4).…”

“…Chemical Synthesis, MIC determination against Mycobacterium tuberculosis H37Rv, Crystal data (including structure refinement details) of CN01, the spectra (including 1 HNMR, 13 CNMR and HRMS), the details about DFT analysis, molecular dynamics simulation are available in the supporting information.…”

[2-Chloro-3-nitro-5-(trifluoromethyl)phenyl](piperidin-1-yl)methanone: structural characterization of a side product in benzothiazinone synthesis

“…1,3-Benzothiazin-4-ones (BTZs) are promising anti-tuberculosis drug candidates, some of which have already reached clinical trials (Mikušová et al, 2014;Makarov & Mikušová , 2020). Various methods for the synthesis of BTZs have been reported (Makarov et al, 2007;Moellmann et al, 2009;Makarov, 2011;Rudolph, 2014;Rudolph et al, 2016;Zhang & Aldrich, 2019). In the original synthesis, 2-chlorobenzoyl chloride derivatives are reacted with ammonium or alkali metal thiocyanates to form the corresponding 2-chlorobenzoyl isothiocyanates (Makarov et al, 2007;Moellmann et al, 2009).…”

8-cyanobenzothiazinone analogs with potent antitubercular activity

“…Subsequent nitro reduction with iron powder in aqueous ethanol provided aniline 3 that was smoothly converted to aryl nitrile 4 through diazotization followed by Sandmeyer reaction with CuCN. Formation of the resultant benzamide derivative 5 was accomplished under mild conditions employing di-tert-butyl dicarbonate and ammonium bicarbonate [ 41 ]. Condensation of benzamide 5 with a variety of sodium carbodithioates 6a–i in DMF through nucleophilic aromatic substitution followed by intramolecular cyclization and dehydrosulfidation yielded target compounds 1a–i in good yields without competitive reaction with the nitrile [ 13 , 42 ].…”