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

Abstract

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.

Keywords:

• Pyrimidine derivatives
• antitubercular activity
• molecular docking study

Disclosure statement

No conflict of interest was reported by the authors.

Additional information

Funding

The authors are thankful to the Chairman, Department of Chemistry, Kuvempu University, Shankaraghatta for providing the laboratory facilities and University of Mysore for providing spectral data. The authors also thankful to UGC-BSR research start-up-grant [No: F.30-486/2019(BSR)] for supporting instrumental facility.