Evidence map›Paper›PMID 40878614›Full record

ArticleFuture medicinal chemistry2025

Discovery of new thiadiazole-based VEGFR-2 inhibitors: design, synthesis, cytotoxicity, and apoptosis induction.

Eslam B Elkaeed, Walid E Elgammal, Hazem Elkady, Hazem A Mahdy, Aisha A Alsfouk, Dalal Z Husein, Omar A Soliman, Mariam Omara, Ibrahim H Eissa, Ahmed M Metwaly

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Article in Future medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

10 authors.

Eslam B ElkaeedDepartment of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
Walid E ElgammalDepartment of Chemistry, Faculty of Science, Al-Azhar University, Cairo, Egypt.
Hazem ElkadyPharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
Hazem A MahdyPharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
Aisha A AlsfoukDepartment of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.ORCID 0000-0003-4497-5013
Dalal Z HuseinChemistry Department, Faculty of Science, New Valley University, El-Kharja, Egypt.
Omar A SolimanDepartment of Clinical Pharmacy, Alexandria University Main Teaching Hospital, Alexandria, Egypt.
Mariam OmaraDepartment of Pharmaceutical Organic Chemistry, College of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
Ibrahim H EissaPharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
Ahmed M MetwalyPharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundVascular endothelial growth factor receptor-2 (VEGFR-2) is a validated target in cancer therapy. However, approved inhibitors like sorafenib are often limited by off-target toxicity and resistance. This study aimed to develop novel thiadiazole-based VEGFR-2 inhibitors with improved selectivity and safer profiles.

methodsA series of 2,3-dihydro-1,3,4-thiadiazole derivatives was rationally designed, synthesized, and structurally characterized. In vitro cytotoxicity was assessed against MCF-7, HepG-2, HCT-116, and normal WI-38 cells. Mechanistic assays included flow cytometry for cell cycle and apoptosis, and ELISA for caspase-3, Bcl-2, and Bax expression. Molecular docking, 200-ns molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and in silico toxicity profiling supported experimental findings.

resultsCompound 11a exhibited the most potent and selective activity (IC₅₀: 9.49 µM for MCF-7, 12.89 µM for HepG-2; SI > 3). It induced >70% apoptosis and dual-phase (S and G2/M) cell cycle arrest. VEGFR-2 inhibition (IC₅₀ = 0.055 µM) was comparable to sorafenib. Computational studies confirmed stable binding at VEGFR-2 active sites.

conclusionCompound 11a is a promising thiadiazole-based candidate with notable in vitro potency, selectivity, and mechanistic activity, supporting its potential for further pharmacokinetics/toxicity evaluation and structural refinement as a VEGFR-2-targeted agent.

Indexed as

Antineoplastic AgentsApoptosisDrug DesignDrug DiscoveryProtein Kinase InhibitorsThiadiazolesVascular Endothelial Growth Factor Receptor-2Cell Line, TumorCell ProliferationDrug Screening Assays, AntitumorHumansMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureStructure-Activity RelationshipAntineoplastic AgentsKDR protein, humanProtein Kinase InhibitorsThiadiazolesVascular Endothelial Growth Factor Receptor-2breast cancerDocking studiesMD simulationsThiadiazole derivativesVEGFR-2 inhibitors

Identifiers

PMID40878614
PMCPMC12582049

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.