Synthesis, Structure–Activity Relationship, and Mechanistic Studies of Aminoquinazolinones Displaying Antimycobacterial Activity

Abstract

Phenotypic whole-cell screening against Mycobacterium tuberculosis ( Mtb ) in glycerol–alanine–salts supplemented with Tween 80 and iron (GASTE-Fe) media led to the identification of a 2-aminoquinazolinone hit compound, sulfone 1 which was optimized for solubility by replacing the sulfone moiety with a sulfoxide 2 . The synthesis and structure–activity relationship (SAR) studies identified several compounds with potent antimycobacterial activity, which were metabolically stable and noncytotoxic. Compound 2 displayed favorable in vitro properties and was therefore selected for in vivo pharmacokinetic (PK) studies where it was found to be extensively metabolized to the sulfone 1 . Both derivatives exhibited promising PK parameters; however, when 2 was evaluated for in vivo efficacy in an acute TB infection mouse model, it was found to be inactive. In order to understand the in vitro and in vivo discrepancy, compound 2 was subsequently retested in vitro using different Mtb strains cultured in different media. This revealed that activity was only observed in media containing glycerol and led to the hypothesis that glycerol was not used as a primary carbon source by Mtb in the mouse lungs, as has previously been observed. Support for this hypothesis was provided by spontaneous-resistant mutant generation and whole genome sequencing studies, which revealed mutations mapping to glycerol metabolizing genes indicating that the 2-aminoquinazolinones kill Mtb in vitro via a glycerol-dependent mechanism of action.

Construction of lux-based promoter-reporter platforms in Mycobacterium bovis BCG for screening of drug repurposing small-molecule compounds as new anti-tuberculosis drugs

“…CysA2 is an essential regulator in the sulfur assimilation pathway [23] and its dysregulation could impair M. tuberculosis survival in macrophages [24]. In parallel, a previous study demonstrated that inhibition of glycerol metabolism by 2-aminoquinazolinones via glpD2 down-regulation could kill M. tuberculosis in vitro [25]. Taken together, dysfunctions of sulfur and glycerol metabolism are possible drug mechanisms for Ebselen.…”

Strategies to Combat Multi-Drug Resistance in Tuberculosis

“… 2020 6 1951 1964 . 4 This work highlights the importance of performing secondary screening in multiple growth media.…”

“…In continuation of our TB drug discovery efforts, a whole-cell cross-screening against Mtb identified the 2-aminoquinazolinone series as an attractive chemotype to prosecute. 4 Originally, the 2-aminoquinazolinones were synthesized for evaluation against the human malaria parasite Plasmodium falciparum , based on their structural similarity to a previously discovered antimalarial 2-aminopyridine series in our lab. 29 The hit compound 6 exhibited good in vitro potency against Mtb but low solubility (MIC, 0.24 μM; solubility, <5 μM).…”

Anti-TB evaluation of novel 2,3-dihydroquinazolin-4(1H)-ones and in silico studies of the active compounds

“…2,3-dihydroquinazolin-4(1H)-one is one of the derivatives of quinazoline that possesses broad range of biological, medicinal and pharmacological activities such as anti-tumor, antibiotic, anti-tubercular, anti-defibrillatory, anti-pyretic, analgesic, anti-hypertonic, diuretic, anti-histamine, anti-depressant, vasodilating agents and many more [13][14][15][16][17][18][19][20][21][22]. Since 2,3dihydroquinazolin-4(1H)-one acquire different biological applications, in the present work, we made an attempt to synthesize some novel 2,3-dihydroquinazolin-4(1H)-ones with an aim to get probable novel anti-TB agent(s).…”