Toxicity of 3 and 3,6-disubstituted coumarins: A computational approach

Abstract

Fifteen reported coumarin molecules with substitutions at positions C-3 and C-6 are investigated using density functional theory (DFT) and time dependent DFT (TD-DFT for their growth inhibitory potential. The coumarins are categorized in three different groups with respect to their toxicity values. The experimentally determined toxicity values, like minimum inhibitory concentration (MIC) and lethal dose 50 (LD50) are correlated to the calculated global molecular descriptors. A direct correlation was observed for MIC values with electrophilicity index and vertical excitation, whereas an inverse trend was obtained with the band gap and electron correlation. In the case of LD50 values, a direct trend was noticed with chemical hardness and electron correlation, while an inverse relationship was observed with chemical potential, vertical excitation, first and second order hyperpolarizability. The trends obtained for the MIC values suggest that the coumarin 4 in group 1 with –NO2 substituent on C-6 position exhibits the highest toxicity, while in group 2, coumarin 1 with no substituent on C-6 position displays relatively lower toxicity, and coumarin 3 with CH2 4-OMeC6H4 substituent on side chain of C-6 position possesses higher toxicity. Similarly, the LD50 values highlighted that coumarin 2 having –COOEt substituent at C-3 position was the most toxic compound in group 2, and coumarin 8 and 10 (t-Butyl group on side chain of C-6 position of coumarin 8 and CH2COOEt group on side chain of coumarin 10) exhibited the highest toxicities in group 3. Molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies were conducted for the compounds under investigation. The molecular docking analysis unveiled a strong affinity of the coumarin compounds for the primary targets of DNA gyrase B kinase, with robust binding abilities indicated by energetically stable scores ranging from −10.1 to −7.2 kcal/mol.