Design, synthesis, in silico toxicity prediction, molecular docking, and evaluation of novel pyrazole derivatives as potential antiproliferative agents

• Published in: EXCLI journal Vol. 15; pp. 187 - 202
• Main Authors: Ravula, Parameshwar, Vamaraju, Harinadha Babu, Paturi, Manichandrika, Chandra Jn, Narendra Sharath, Kolli, Swetha
• Format: Journal Article
• Language: English
• Published: Germany Leibniz Research Centre for Working Environment and Human Factors 01.01.2016
• Subjects: Original; molecular modeling; pyrazolyl tetrazole acetic acids; VEGFR-2; antiproliferative activity
• ISSN: 1611-2156; 1611-2156
• DOI: 10.17179/excli2016-103

A new series of pyrazole derivatives were designed by docking into vascular endothelial growth factor receptor-2 (VEGFR-2) kinase active site. The designed compounds were synthesized and evaluated for in vitro antiproliferative activity against HT-29 colon and PC-3 prostate cancer cell lines, and angioinhibitory activity in chorioallantoic membrane (CAM) model. Based on the obtained antiproliferative activity results of in vitro and CAM assay, compounds 4b, 4c, 4f, 5b, 5c and 5f were selected, and tested for anticancer activity using in vivo ehrlich ascites carcinoma (EAC) bearing mice. Compound 5c showed the highest in vitro antiproliferative activity against HT-29 and PC-3 with IC50 values of 6.43 µM and 9.83 µM respectively and comparable to reference drug Doxorubicin. Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively. Moreover, compound 5c demonstrated significant reduction of microvessel density (MVD) in CAM assay. In silico prediction of toxicities, and drug score profiles of designed compounds are promising. A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity.