New diarylureas and diarylamides containing 1,3,4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition, and molecular docking studies

Synthesis of a new series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold is described. Their in vitro antiproliferative activities against 9 human melanoma cell lines were tested. Compounds 12, 13, 15, and 21–23 showed the highest potency against A375P melanoma cell line. In addition, compounds 10–15 and 19–24 showed high potency over the NCI 8 tested melanoma cell-lines panel. The IC50 values for compound 23 were 0.36 μM and 0.84 μM over LOX IMVI and M14 cell lines, respectively. Compounds 21 and 23 showed high, dose-dependent inhibition of ERK kinase. Virtual screening was carried out through docking of compound 21 into the domain of V600E-B-RAF and the binding mode was studied.

A series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold was synthesized. Their in vitro antiproliferative activities against nine human melanoma cell lines, ERK kinase inhibition, and docking into V600E-B-RAF were evaluated.Figure optionsDownload as PowerPoint slideHighlights
► New diarylureas and diarylamides with 1,3,4-triarylpyrazole scaffold were synthesized.
► Their in vitro antiproliferative activities against nine human melanoma cell lines were tested.
► Compounds 12, 13, 15, 21–23 showed the highest potency against A375P human melanoma cell line.
► The IC50 of compound 23 was in sub-micromolar scale over 2 cell lines.
► Compound 21 showed high ERK kinase inhibitory activity and its in silico binding mode with V600E-B-RAF was studied.