Synthesis, antitubercular activity and molecular docking study of substituted [1,3]dioxino[4,5-d]pyrimidine derivatives via facile CAN catalyzed Biginelli reaction

We have developed a simple and convenient method for the synthesis of substituted-aryllidine-2,2-dimethyl-7-thioxo/oxo-4H-[1,3]dioxino[4,5-d]pyrimidine derivatives (4a-g) via one-pot Biginelli reaction of Meldrum's acid (1), indole-3-carbaldehyde/thiophene-2-carbaldehyde/2-chloro-quinoline-3-carbaldehyde (2) and amines (3) in aqueous ethanol in the presence of a catalytic amount of CAN. The obtained pyrimidine hybrids were screened for their antimycobacterial activity against Mycobacterium tuberculi H37RV strain. The antimycobacterial results showed that compounds 4a and 4b exhibited excellent activity with MIC value of 1.6 µg/mL, four-fold greater than the standard streptomycin (6.24 µg/mL), while compounds (4c-g) showed lower efficacy. To study the interaction between the synthesized compounds and receptor, the compounds 4a, 4b, 4c, and 4d were studied for molecular docking on the enzyme enoyl-acyl carrier protein reductase (enoyl-ACP reductase) and the compounds 4a and 4b have emerged as active antitubercular agents with least binding energy -9.4 kcal/mol and -9.3 kcal/mol respectively.