Synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives and exploring molecular and cytotoxic properties based on DFT and molecular docking studies

Abstract

• Dicyclic 1,4-dihydropyran[2,3- c ]pyrazole-5-carbonitrile derivatives were synthesized as potential anticancer agents. • The cytotoxic activity was tested against PC-3, SKOV-3, HeLa and A549 cell lines. • The frontier molecular orbitals, electron affinity, ionization potential and molecular electrostatic potential (MEP) were studied. • The molecular docking was accomplished onto thymidylate synthase (TS) protein was discussed. One-pot multicomponent reaction of ethyl 3-oxobutanoate or ethyl 3-oxo-3-phenylpropanoate, hydrazine hydrate, malononitrile, various aldehydes in ethanolic piperidine solution under Microwave irradiation gave 6-amino-4-aryl/hetaryl-3-methyl/pheny-1,4-dihydropyran[2,3- c ]pyrazole-5-carbonitriles. The structures of these compounds were established on the basis of IR, 1 H NMR, 13 C NMR, 13 C NMR-APT, MS data and elemental analysis. Furthermore, the cytotoxic activity properties were evaluated against the human cancer cell lines PC-3, SKOV-3, HeLa and A549 in comparison to the positive controls Vinblastine and Doxorubicin, employing the viability assay. The obtained results confirmed that some of the tested molecules revealed strong and selective cytotoxic activities against the four cancer cell lines. Herein, frontier molecular orbitals (FMO), electron affinity (EA), ionization potential (IP) and molecular electrostatic potential (MEP) was carried out to understand the active sites and biological active nature of pyrano[2,3- c ]pyrazole synthesized compounds. A systematic study was performed then frontier molecular orbitals energies, active sites and molecular descriptors were compared with reference drug. The molecular docking was accomplished onto thymidylate synthase (TS) protein. The compounds with highest efficiency exhibited promising binding interactions and binding affinities into active site.