Jul 2026· Computational biology and chemistry· Vol 125, pp.
109258
· 0 citations· 42 references
Medicine
TL;DR
The design, synthesis, and comprehensive evaluation of novel sulfonyl hydrazone derivatives (2a-o) that strategically combine two privileged scaffolds with complementary anticancer mechanisms are reported, highlighting sulfonyl hydrazone derivatives as promising scaffolds for anticancer drug development and identifying compound 2 h as a potential hit candidate for further structural optimization targeting cathepsin B.
Abstract
Sulfonyl hydrazone derivatives represent promising scaffolds in cancer progression, immune evasion, and treatment resistance. However, it remains underexploited due to the challenge of achieving selective inhibition without harming normal cellular functions. This study reports the design, synthesis, and comprehensive evaluation of novel sulfonyl hydrazone derivatives (2a-o) that strategically combine two privileged scaffolds with complementary anticancer mechanisms. Following complete structural characterization by FT-IR and NMR spectroscopy, an integrated experimental-computational workflow enabled the identification and mechanistic evaluation of compound 2 h as a promising hit candidate. Compound 2 h was selected for its favorable balance of anticancer potency, selectivity, and drug-likeness. In vitro evaluation against the human glioblastoma cell line (U87) and the human pancreatic cancer cell line (T3M4) demonstrated that sulfonyl hydrazone derivatives exhibit moderate anticancer activity. The compound 2 h demonstrates moderate antiproliferative activity with an IC50 of 67.60 ± 4.02 µM, whereas it affects normal human umbilical vein endothelial cells (HUVECs) with an IC50 of 194.91 ± 7,00 µM. Furthermore, in silico assessments indicated favorable physicochemical and absorption properties, alongside predicted liabilities to be addressed in future optimization. To elucidate the molecular mechanism underlying the observed anticancer activity, an integrated computational workflow including target prediction, molecular docking, and deep-learning-based structural modeling was employed. These analyses nominated cathepsin B (CTSB) as the most plausible candidate target, pending experimental confirmation, supported by its cancer-selective expression and favorable binding interactions with compound 2 h within the catalytic active site. The results highlight sulfonyl hydrazone derivatives as promising scaffolds for anticancer drug development and identify compound 2 h as a potential hit candidate for further structural optimization targeting cathepsin B.
Findings identify compound 7e as a promising VEGFR-2-targeted anticancer lead with strong enzymatic inhibition, potent cytotoxicity, and a well-supported mechanistic profile integrating experimental and computational evidence.
A. Metwaly, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
These findings highlight benzimidazole derivatives, particularly 16a and 17b and their nanoparticle formulations, as promising anticancer candidates, driven primarily by strong cellular potency and favorable safety, substantiating their potential as lead candidates for further optimization and therapeutic development.
Mai Montaser Abdullah, R. Hathout, Reham S. Elezaby et al.· RSC Medicinal Chemistry· 0 citations
The present investigation was undertaken to design, synthesize, characterize and biologically evaluate novel heterocyclic derivatives with the objective of discovering new small-molecule leads possessing analgesic, anti-inflammatory and anticancer potential, supported by molecular docking-based mechanistic insight. Major heterocyclic systems were explored: 7-Azaindole / 7-azaisatin–derived semicarbazide hybrids (VIIa–l and selected analogues) for anticancer screening. All synthesized compounds were structurally confirmed through IR, ¹H-NMR, ¹³C-NMR, LC–MS and elemental analysis, with melting-point and TLC supporting purity. The synthetic strategies used versatile heterocyclic chemistry enabling substitution-dependent structure–activity evaluation. Acute oral toxicity studies demonstrated wide safety margins, with no mortality up to high dose levels in rodents, suggesting good tolerability. Pharmacological Findings For the azaindole / azaisatin semicarbazide derivatives: In vivo anticancer screening using Ehrlich Ascites Carcinoma demonstrated significant tumor-growth suppression, improved survival indices, and reduced viable cell counts for selected compounds. MTT cytotoxicity studies confirmed dose-dependent antiproliferative activity against HeLa and HCT-15 cell lines, with micromolar-level IC₅₀ values for the most active molecules (e.g., XXV and XXIIIb). Docking against DHFR and COX-2 provided mechanistic evidence of favorable receptor complementarity. Collectively, the findings validate the medicinal-chemistry hypothesis that heterocyclic hybridization and rational substitution drive potency, binding affinity, and biological response across multiple pharmacological models.
Shaik Kaleem, K. Chaitanya prasad, K. Nagasree et al.· International journal of che...· 0 citations
Cancer continuing to present a serious global health threat, creating an urgent demand for new and effective anticancer candidates. In this study, several novel acridone derivatives were synthesized and characterized by 1H NMR, 13C NMR, HRMS and FT‐IR, and their in vitro anticancer activity was evaluated combined with systematic theoretical calculations. Of these derivatives, 6a demonstrated antiproliferative activity against the HGC‐27 gastric cancer cell line (IC50 = 4.86 µM) in comparison with the HeLa cervical cancer cell line and the HCT116 colon carcinoma cell line. Furthermore, morphological assessment under an inverted microscope revealed that it induced apoptosis like morphological changes. Density functional theory calculations were employed to gain insight into the electronic structure and intramolecular interactions of these compounds. Molecular docking studies revealed that compound 6a binds to the gastric cancer target protein (4OUM) through hydrogen bonds with Arg1106 and Asn1057, which contribute to its enhanced binding affinity (−5.59 kcal/mol). This binding energy is consistent with its potent antiproliferative activity, establishing a correlation between the computational prediction and the experimental observation. Taken together, these results indicate that compound 6a represents a promising lead for the development of novel anticancer agents.
Shu-Lin Zhang, Jia-Yan Chen, Jia-Jia Lan et al.· Chemistry and Biodiversity· 0 citations
Sulfonamides represent one of the most versatile scaffolds in medicinal chemistry. Since their introduction as the first synthetic antibacterial agents in the 1930s, the sulfonamide functional group (-SO₂NR₂) has enabled extensive structural diversification, leading to compounds with broad therapeutic applications. In recent years, sulfonamide derivatives have gained renewed attention in drug discovery due to their roles in antimicrobial, anticancer, antimalarial, antiviral, antiinflammatory, antidiabetic, and antioxidant therapies. This review provides a comprehensive and structured overview of modern synthetic strategies for sulfonamide construction, including classical sulfonyl chloride-amine coupling, metal-catalyzed synthesis of sulfonamides, microwave-assisted synthesis, and other advanced methodologies that enable efficient access to structurally diverse derivatives. In parallel, recent advances in the biological evaluation of sulfonamide analogues are discussed, with emphasis on emerging pharmacological targets and mechanistic insights, such as enzyme inhibition, metabolic interference, and receptor modulation. By correlating synthetic approaches with observed biological activities, this review highlights the structure-activity relationships that guide rational drug design. Current challenges, research gaps, and future perspectives for sulfonamide-based therapeutics are also outlined. Collectively, the adaptability of the sulfonamide scaffold, combined with continued advances in synthetic chemistry and biological screening, underscores its sustained importance in the development of next-generation therapeutic agents.
Emmanuel Chinedu Nnadi, Vivian Ifeoma Okonkwo, Faith Temitope Elijah et al.· Mini-Reviews in Medical Chem...· 0 citations
A series of innovative 1,2,4-oxadiazole-functionalized funtumine derivatives were designed, synthesized, and assessed for their antiproliferative effects on HCT116, HeLa, and HepG2 human cancer cell lines to discover new natural product-derived anticancer agents. The majority of these compounds demonstrated favorable anticancer efficacy, with compound 4m exhibiting better activity against HepG2 cells (IC
50
= 3.15
μ
M) while maintaining low cytotoxicity towards normal human cells. Mechanistic investigations indicated that 4m triggered apoptosis in a dose-dependent manner and modified the transcriptomic profile of HepG2 cells, affecting crucial pathways such as chemical carcinogenesis-DNA adducts, steroid hormone biosynthesis, and cytochrome P450-mediated xenobiotic metabolism. Protein-protein interaction network analysis identified cytochrome P450 1A2 (CYP1A2) and UDP glucuronosyltransferase family 2 member B11 (UGT2B11) as potential targets, which were corroborated by molecular docking studies revealing strong binding interactions with 4 m. Density functional theory calculations revealed the electronic properties and reactivity of 4m, highlighting its potential for targeted engagement. These results highlight 4m as a promising, low-toxicity anticancer candidate worthy of further development.
Longyun Zhang, Yafang Chen, Ming-Jiang Lu et al.· Arabian Journal of Chemistry· 0 citations