Identification of novel benzothiopyranone compounds against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones

Abstract

In this study, three novel series of benzoxazinone, benzothiopyranone and benzopyranone derivatives were designed and synthesized through scaffold morphing from benzothiazinones targeting DprE1. All compounds were evaluated for their in vitro activities against Mycobacterium tuberculosis (M. tuberculosis) and cytotoxicity against Vero cell line. Among the three series, the benzothiopyranone series displayed excellent antimycobacterial activity and low cytotoxicity. Compound 6b exhibited potent in vitro activity against both drug-susceptible and drug-resistant M. tuberculosis clinical strains with MICs < 0.016 μg/mL. In addition, compound 6b demonstrated excellent ADME/T and PK properties and potent in vivo efficacy with bactericidal activity comparable to human equivalent dose of isoniazid (INH) in an acute mouse model of TB. Compound 6b which exhibits good inhibitory activity against DprE1 is under evaluation as a potential drug candidate for the treatment of tuberculosis. The current study provided new insight into the structural and pharmacological requirements for DprE1 inhibitors as potent antitubercular agents.

Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties

“…20 Nucleophilic aromatic substitution of 16 with 2chlorobenzamide derivative 17 followed by intramolecular cyclization provided 1 in 80% yield, which was purified by silica gel chromatography. 13 Consistent with a decrease in planarity, the melting point of 1 (mp 126−128°C) was significantly decreased compared to PBTZ169 (mp 176−178°C ). 5 Compounds 3−4 and 6−12 were prepared in analogous fashion as described in the Supporting Information.…”

Benzopyran-Core as an Antimycobacterial Agent

“…However, many analogs which inhibited the growth of M. tuberculosis in the 0.6-5µg/mL range (including chromane 34) turned out to be cytotoxic on vero cells at the same concentration range. Li et al [76] described the synthesis of 2-azacyclo-5trifluoromethyl-8-nitrobenzopyran-4-one derivatives (35)(36)(37) and assessed their minimum inhibitory concentration (MIC) to Mtb H 37 Rv strain using the MABA method. The compounds exhibited good antitubercular activity, which is comparable with standard drugs, but were inferior to their benzothiopyran-4-one counterparts (Figure 13).…”

An efficient and concise access to 2-amino-4H-benzothiopyran-4-one derivatives

“…Benzothiopyranones are a class of molecules displaying biological activities in part due to their structural relationship with benzopyranones, which are known as one privileged scaffold in medicinal chemistry [1]. The corresponding 2-aminobenzothiopyranones are molecules of high interest as they have remarkable anticancer, antifungal and antitubercular activities [2–5].…”

“…However, for this reaction an adjacent electron-withdrawing group such as a carbonyl or triazole group is required at the 3-position of the thiochromone ring (method D and E, Scheme 1) [3–4]. Very recently, our group obtained a series of 2-aminobenzothiopyranones containing 8-nitro and 6-trifluoromethyl substituents in low to moderate yields through the transformation of a 2-methylthio substituent under harsh conditions (method F, Scheme 1) [5]. In addition, the nucleophile imidazole could also react with 3-bromobenzothiopyranones to afford 2-imidazolylbenzothiopyranones [10].…”

“…In our continuing efforts to discover novel 2-amino-4 H -benzothiopyran-4-ones with activity against Mycobacterium tuberculosis ( Mtb ) [5], we aim to develop an improved and efficient synthetic route by thoroughly evaluating the feasibility of the elimination of sulfide, sulfinyl or sulfonyl groups at the 2-position of the benzothiopyranone scaffold without requiring an adjacent electron-withdrawing substituent at the 3-position.…”