Structure-activity relationship study of a new class of 2-amino-3,4-dihydroquinazolines as antitubercular agents

The discovery of novel chemical matter with antitubercular activity that could feed into the tuberculosis (TB) drug discovery pipeline addresses the need to develop novel drugs that inhibit growth of both drug sensitive and drug resistant strains of Mycobacterium tuberculosis ( Mtb ). Whole cell-based screening yielded a 2-amino-3,4-dihydroquinazoline core as a novel hit and preliminary structure-activity relationship (SAR) study around the structure was performed with 16 analogs derivatized in diverse structural points to determine the pharmacophore. The promising antitubercular activity of L16 , the lead compound of this series was shown to be non-toxic to eukaryotic cells and had a novel mechanism of action since it lacked activity against known promiscuous targets of the pathogen. Additionally, L16 retained activity against different drug-resistant clinical strains. Although the MIC was improved significantly without any cytotoxicity, flat SAR, no identifiable target and equivalent activities of the two stereoisomers of the hit compound led us to abandon further optimization of this series. • Whole cell-based screening yielded a 2-amino-3,4-dihydroquinazoline core as a novel hit in TB drug discovery. • For SAR study, 16 analogs derivatized in diverse structural points were synthesized. • Compound L16 showed promising activity without cytotoxicity in the test of not only normal strains but also different drug-resistant clinical strains.