Design, synthesis, characterization, crystal structure, Hirshfeld surface analysis, DFT calculations, anticancer, angiogenic properties of new pyrazole carboxamide derivatives

Abstract

The present study demonstrate the utility of a reverse ligand similarity based approach to identify potential targets for a new series of synthesized pyrazole carboxamides that shows potent anticancer activities against MCF-7 cells compared to other structurally related molecules and controls. Molecular docking studies revealed that the compound 5b interacted very strongly with human estrogen receptor with docking score of -8.82kcal/mol. In case of hERα-LBD, it interacted very well via hydrogen bond with Thr347 with docking score of -8.19 kcal/mol and very good binding with Asp351 via both hydrogen bonding and salt bridge. These results indicate that compound 5b act as better inhibitor for estrogen receptors comparable with the standard inhibitor tamoxifen. Further, ADMET studies reveal that the synthesized compounds have good ADME properties as compared with the data from 95% of drugs readily available in the market. The compound possesses three dimensional supramolecular self-assembly, in which N—H•••O bonds connects the molecules and build up two dimensional arrays, which are extended to 3D network through C—H•••Cg and C—Cl•••Cg interactions. The structure also exhibits π•••π stacking interactions, which contributes to the crystal packing. The Hirshfeld surface analysis was carried out to quantify the intermolecular interactions involved in the crystalline environment. We further optimized the molecular geometry of the compound 5d by DFT method with B3LYP hybrid functional and 6-311+G(d,p) basis set. The optimized structure is in good agreement with the experimental findings. The electrostatic potential map was plotted to understand the energy distribution and chemical reactive regions of the molecule.