Green synthesis of spiro-barbiturates: advancing sustainable chemistry and drug design research

Abstract

Through this research, we have established an environmentally friendly and sustainable approach for the synthesis of spirobarbiturate (SB) derivatives, which hold significant potential in the field of medicinal chemistry. The methodology emphasizes the design of safer synthetic routes, judicious selection of reagents, waste minimization, and the advantages of using green solvents. The spirobarbiturate derivatives were synthesized utilizing a one-pot, three-component reaction of arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-triones with dimethylacetylenedicarboxylate and triphenylphosphine in cyclopentyl methyl ether (CPME), a bio-based green solvent, under room temperature conditions. The synthesized compounds were characterized and in silico assessed by molecular docking and molecular dynamics (MD) simulations using GABA(A) and NMDA receptors. The methoxy-substituted spirobarbiturate showed the strongest binding and highest dynamic stability with the GABA(A) receptor, as determined by MMGBSA free energy calculations. The presented methodology highlights the importance of employing eco-friendly synthetic techniques in drug design research while the results of docking and simulation studies are indicative of exploring the potential use of synthesized compounds as neuronal drugs. Furthermore, this paper also provides the methodology of calculations for the ‘green quotient’ of the protocol employed, thereby advocating the promotion of green chemistry practices and skills in the newer generation of chemists.