A novel sulfamoylphenyl-dihydro-thiadiazole derivative as a dual EGFR and carbonic anhydrase inhibitor for cancer therapy

Sep 23, 2026

Uploaded by Elsa

A novel sulfamoylphenyl-dihydro-thiadiazole derivative (compound 14) is designed and synthesized as a dual inhibitor targeting EGFR and human carbonic anhydrases hCA_IX and hCA_XII. Density functional theory, molecular docking, and molecular dynamics simulations support stable binding, favorable interactions, and defined reactivity. Compound 14 shows potent EGFR inhibition (IC50 10.12 ± 0.29 nM) and strong hCA inhibition (IC50 79 ± 1.2 nM; 58 ± 0.9 nM), with selective cytotoxicity against cancer cells versus Vero cells. Apoptosis and cell-cycle arrest results indicate effective cancer cell death, and in silico toxicology suggests acceptable safety and encouraging in vivo potential.

LanguageEnglish

CategoryHealthcare

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Pages36

Reading Time1 h 31 min

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Abstract

Introduction

OPEN ACCESS Citation: Eissa IH, Elkady H, Elgammal WE, Mahdy HA, Husein DZ, Amin FG, et al. (2025) A novel sulfamoylphenyl-dihydro-thiadiazole derivative as a dual EGFR and carbonic anhydrase inhibitor for cancer therapy. PLoSOne 20(9): e0328305. [https://doi.org/10.1371/](https://doi.org/10.1371/)[ ](https://doi.org/10.1371/)[journal.pone.0328305](journal.pone.0328305) Editor: Afzal Basha Shaik, Vignan Pharmacy College, INDIA Received: March 24, 2025 Accepted: June 28, 2025 Published: September 4, 2025 Copyright: © 2025 Eissa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data availability statement: All relevant data are within the paper and its Supporting Information files. Funding: This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number RESEARCH ARTICLE A novel sulfamoylphenyl-dihydro-thiadiazole derivative as a dual EGFR and carbonic anhydrase inhibitor for cancer therapy Ibrahim H. Eissa1*, Hazem Elkady1*, Walid E. Elgammal2, Hazem A. Mahdy1, Dalal Z. Husein3, Fatma G. Amin4, Asmaa A. A. Elsheshiny5, Shimaa. S. Abdelfattah6 , Aisha A. Alsfouk7, Eslam B. Elkaeed8, Ahmed M. Metwaly9* 1 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt, 2 Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt, 3 Chemistry Department, Faculty of Science, New Valley University, El-Kharja, Egypt, 4 Physics Department, Faculty of Science, Alexandria University, Alexandria, Egypt, 5 Biophysics Branch, Physics Department, Faculty of Science (girls), Al-Azhar University, Nasr City, Cairo, Egypt, 6 Physics Department, Faculty of Science, Al-Azhar University (Girl’s Branch), Cairo, Egypt, 7 Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia, 8 Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia, 9 Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt * [Ibrahimeissa@azhar.edu.eg](Ibrahimeissa@azhar.edu.eg) (IHE); [ametwaly@azhar.edu.eg](ametwaly@azhar.edu.eg) (AMM); [Hazemelkady@azhar.edu.eg](Hazemelkady@azhar.edu.eg) (HE) Abstract A novel sulfamoylphenyl-dihydro-thiadiazole derivative (compound 14) has been designed and synthesized as a dual inhibitor targeting EGFR and human carbonic anhydrases (hCA_IX and hCA_XII) . Computational studies, including density functional theory (DFT), molecular docking, and molecular dynamics simulations, confirmed its stability, favorable binding interactions, and reactivity profiles. Compound 14 showed potent inhibition of EGFR (IC₅₀ = 10.12 ± 0.29 nM), hCA_IX and hCA_XII (IC₅₀ = 79 ± 1.2 nM and 58 ± 0.9 nM, respectively) . Cytotoxicity assays demonstrated selective activity against cancer cells, with IC₅₀ values of 16.13 µM in MDA-MB-231 and 22.57 µM in MCF-7 cells, compared to 148.32 µM in non-cancerous Vero cells. Compared to acetazolamide, compound 14 exhibited improved selectivity for cancer cells. Apoptosis studies revealed significant cell death in MDA-MB-231 cells, with early and late apoptosis rates of 22.50% and 58.27%, respectively, alongside a marked G1-phase cell cycle arrest (49 . 10% in treated cells vs. 44.98% in controls) . Insilico toxicological evaluations indicated a favorable safety profile, with low irritancy and acceptable rat oral LD₅₀ (15 .81 mg/kg) and carcinogenic potency (TD₅₀ = 36.95) . Compound 14’s potent dual inhibition and selective cytotoxicity make it a promising candidate for further optimization and in vivo studies. PLOS One | [https://doi.org/10.1371/journal.pone.0328305](https://doi.org/10.1371/journal.pone.

FAQs

What molecular targets does compound 14 inhibit?

Compound 14 is designed as a dual inhibitor of EGFR and human carbonic anhydrases hCA_IX and hCA_XII.

Which computational methods supported compound 14’s activity?

Density functional theory (DFT), molecular docking, and molecular dynamics simulations were used to confirm stability, binding interactions, and reactivity profiles.

How does compound 14 perform in cytotoxicity compared with non-cancerous cells?

It shows selective activity against cancer cell lines (IC50 16.13 µM for MDA-MB-231 and 22.57 µM for MCF-7) compared with 148.32 µM in non-cancerous Vero cells.

Sep 23, 2026

Uploaded by Elsa