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In a search of new potentially active antitubercular agents, here we have initiated with pharmacophore development, virtual screening and molecular docking studies to know flexible binding modes with target cavity of DprE1 enzyme. We have designed and synthesized 6-(trifluoromethyl)-N-(4-oxothiazolidin-3-yl)quinazoline-2-carboxamide derivatives and evaluated for antitubercular activity with specific DprE1 inhibition. The various steps have been completed by performing condensation of 6-(trifluoromethyl)quinazoline-2-carboxylic acid, aromatic aldehydes, methanol, Hydrazine hydrate, -(trifluoromethyl)quinazoline-2-carbohydrazide, 6-(trifluoromethyl)-N′-methylenequinazoline-2-carbohydrazide to obtained 6-(trifluoromethyl)-N-(4-oxothiazolidin-3-yl)quinazoline-2-carboxamide derivatives (3a–r) in better yields. Synthesized derivatives were characterized for their spectral analysis. These compounds have been screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H 37 RV. The compounds 3a (MIC-1.27 μM); 3e (MIC-1.12 μM); 3p (MIC-1.18 μM); and 3r (MIC-0.96 μM); exhibited notable in vitro antitubercular activity compare to the reference standard, Isoniazid. These four compounds were screened for DprE1 enzyme assay. Among those 3e and 3r has shown strong DprE1 inhibition, these compounds were substituted with nitro and hydroxyl group. Image 1 • As per WHO report, tuberculosis (TB) is one of the leading cause of death in infectious disease across the globe. • Molecular modeling approach yielded 18 new quinazoline-2-carboxamide derivatives. • Newly synthesized derivatives studied for In vitro antitubercular activity. • Four compounds have shown better DprE1 Inhibitory Activity. [ABSTRACT FROM AUTHOR]