Discovery of a new potent oxindole multi-kinase inhibitor among a series of designed 3-alkenyl-oxindoles with ancillary carbonic anhydrase inhibitory activity as antiproliferative agents

Rania S M Ismail; Ahmed M El Kerdawy; Dalia H Soliman; Hanan H Georgey; Nagwa M Abdel Gawad; Andrea Angeli; Claudiu T Supuran

doi:10.1186/s13065-023-00994-3

Discovery of a new potent oxindole multi-kinase inhibitor among a series of designed 3-alkenyl-oxindoles with ancillary carbonic anhydrase inhibitory activity as antiproliferative agents

BMC Chem. 2023 Jul 18;17(1):81. doi: 10.1186/s13065-023-00994-3.

Authors

Rania S M Ismail¹, Ahmed M El Kerdawy^{2

3}, Dalia H Soliman^{4

5}, Hanan H Georgey^{2

6}, Nagwa M Abdel Gawad⁷, Andrea Angeli⁸, Claudiu T Supuran⁹

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt. rania-saied@eru.edu.eg.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, School of Pharmacy, Newgiza University (NGU), Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, P.O. Box 11471, Cairo, Egypt.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt. nagwa.abdelgawad@pharma.cu.edu.eg.
⁸ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy.
⁹ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy. claudiu.supuran@unifi.it.

Abstract

An optimization strategy was adopted for designing and synthesizing new series of 2-oxindole conjugates. Selected compounds were evaluated for their antiproliferative effect in vitro against NCI-60 cell lines panel, inhibitory effect on carbonic anhydrase (CA) isoforms (hCAI, II, IX and XII), and protein kinases. Compounds 5 and 7 showed promising inhibitory effects on hCA XII, whereas compound 4d was the most potent inhibitor with low nanomolar CA inhibition against all tested isoforms. These results were rationalized by using molecular docking. Despite its lack of CA inhibitory activity, compound 15c was the most active antiproliferative candidate against most of the 60 cell lines with mean growth inhibition 61.83% and with IC₅₀ values of 4.39, 1.06, and 0.34 nM against MCT-7, DU 145, and HCT-116 cell lines, respectively. To uncover the mechanism of action behind its antiproliferative activity, compound 15c was assessed against a panel of protein kinases (RET, KIT, cMet, VEGFR1,2, FGFR1, PDFGR and BRAF) showing % inhibition of 74%, 31%, 62%, 40%, 73%, 74%, 59%, and 69%, respectively, and IC₅₀ of 1.287, 0.117 and 1.185 μM against FGFR1, VEGFR, and RET kinases, respectively. These results were also explained through molecular docking.

Keywords: Carbonic anhydrase; Design; Docking; Indolin-2-one; Protein kinases; Synthesis.