Anticancer and Cyclooxygenase Inhibitory Activity of Benzylidene Derivatives of Fenobam and its Thio Analogues

Wafa Hourani; Pran Kishore Deb; Maysa Alhawamdeh; Nizar Al-Shari; Pobitra Borah; Lina A Dahabiyeh; Abdulmuttaleb Yousef Jaber; Nefisath P; Shashiprabha S; Jagadeesh Prasad Dasappa; Katharigatta N Venugopala

doi:10.2174/0109298673345068241120045638

Anticancer and Cyclooxygenase Inhibitory Activity of Benzylidene Derivatives of Fenobam and its Thio Analogues

Curr Med Chem. 2024 Dec 16. doi: 10.2174/0109298673345068241120045638. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, Amman 19392, Jordan.
² Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology (BIT), Mesra, Ranchi 835215, India.
³ Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Mutah University, Al-Karak 61710, Jordan.
⁴ Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University. P.O. Box 2713-Doha, Qatar.
⁶ Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India.
⁷ Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Queen Rania St, Amman 11942, Jordan.
⁸ Post Graduate Department of Chemistry, Sri Dharmasthala Manjunatheshwara College (Autonomous), Ujire 571234, India.
⁹ Department of PG Studies and Research in Chemistry, Mangalore University, Mangalagangothri 574199, India.
¹⁰ Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
¹¹ Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban 4001, South Africa.

PMID: 39686634
DOI: 10.2174/0109298673345068241120045638

Abstract

Introduction: A series of benzylidene derivatives of fenobam and its thio analogues (1-22) have been evaluated for their cytotoxicity against breast cancer (MCF-7, MDA-MB-231), ovarian cancer (A2780, SKOV-3) and cervical cancer (HELA) cell lines.

Method: These compounds (1-22) exhibited 72-83% inhibition of Erk activity against the ovarian cancer cell line (A2780). Compounds 3 and 20 showed the highest DNA damage effect in Comet Assay against the A2780 cancer cell line as compared to the other tested analogues (4, 8, 11, 12, and 13) by using % Tail DNA and OTM. Compounds 3, 4, and 11 showed significant activities and selectivity towards COX-2 with 78%, 97%, and 89% inhibition, as compared to 17%, 57%, and 26% inhibition against COX-1 isoenzyme, respectively.

Results: Interestingly, molecular docking scores were also in very good agreement with the experimental results regarding discriminating the selectivity index of the tested compounds against COX-1 & COX-2 enzymes. Further molecular dynamics (MD) simulation study revealed that the most selective compound, 13, binds with the COX-2 enzyme in a similar fashion to that of Rofecoxib, which was further supported by their MD-based free binding energies (MM-GBSA) of -49.76 ± 4.27 kcal/mol, and -44.84 ±3.78 kcal/mol, respectively.

Conclusion: Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.

Keywords: Benzylidene derivatives; COMET assay; COX 1 inhibition; COX 2 inhibition; Erk analysis.; cancer.