Aug 2026· International journal of chemical and pharmaceutical sciences· 0 citations
TL;DR
The findings validate the medicinal-chemistry hypothesis that heterocyclic hybridization and rational substitution drive potency, binding affinity, and biological response across multiple pharmacological models.
Abstract
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.
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
Among the synthesized compounds, PBc1 exhibited the greatest in vitro antiproliferative activity against both MDA-MB-231 and SK-OV-3 cell lines, suggesting that PBc1 is a promising compound for further biological and mechanistic investigation.
Prachita Gauns Dessai, Parixit J. Bhandurge, C. Nazareth et al.· Journal of the Iranian Chemi...· 0 citations
The study was undertaken to design, synthesize, characterize, and evaluate novel imidazole-based oxazolone derivatives (OXA01–OXA09) possessing two pharmacophoric systems with the goal of identifying new analgesic and anti-inflammatory lead compounds. A systematic research plan was followed that included molecular design, multi-step organic synthesis, purification, analytical characterization, in vivo pharmacology, in vitro cytotoxicity, and molecular docking. Oxazolone derivatives were synthesized via cyclodehydration of benzoylglycine intermediates with various substituted aryl aldehydes in acetic anhydride–sodium acetate under catalytic ZnO. All intermediates and final compounds were purified and structurally confirmed by TLC, melting point analysis, IR, ¹H/¹³C NMR, LC–MS, and elemental analysis, confirming successful formation of the intended oxazolone scaffolds. Acute oral toxicity studies in rodents revealed no mortality or severe toxic symptoms up to 2560 mg/kg, indicating high safety margins and LD₅₀ greater than 2560 mg/kg, classifying the compounds as low-toxicity agents. Most derivatives demonstrated dose- and time-dependent analgesic activity, with OXA03, OXA05, OXA07, and OXA09 showing the strongest effects, in some cases comparable to or exceeding standard drugs (indomethacin and diclofenac). Compounds such as OXA08 and OXA02 also demonstrated moderate yet meaningful activity.
K. Girija, K. Prasad, K. Nagasree et al.· International journal of che...· 0 citations
This review highlights the recent emerging therapeutic potential of quinoline-based scaffolds in anticancer drug discovery. A systematic and integrative review methodology was adopted, emphasising recent literature on synthetic strategies, structure-activity relationship (SAR) trends, mechanistic insights and in vitro/in vivo evaluations of quinoline derivatives. Modern synthetic approaches have enabled the efficient construction of structurally diverse quinoline hybrids with enhanced pharmacological profiles. Biological investigations reveal that several quinoline hybrids exhibit potent anticancer activity in low micromolar to submicromolar ranges. Additionally, exceeding the efficacy of standard drugs while demonstrating enhanced selectivity towards cancer cells. Mechanistically, these compounds act through multi-target modulation, induction of apoptosis, mitochondrial dysfunction and cell cycle arrest. SAR analyses indicated that strategic substitutions on the quinoline core and hybridisation with bioactive compounds enhance target binding and efficacy. Furthermore, in silico approaches, including molecular docking and ADME profiling, provide critical support for experimental findings and facilitate rational lead optimisation. Despite promising outcomes, challenges related to drug resistance, toxicity and pharmacokinetics persist. These limitations may be addressed through continuous advancement in the design and optimisation of anticancer-active molecular frameworks. Overall, quinoline hybrids represent a versatile and promising scaffold for the development of next-generation anticancer agents.
Sanjeev Kumar Patel· European journal of medicina...· 0 citations
Background/Objectives: The development of multifunctional small molecules capable of simultaneously addressing cancer progression and antimicrobial resistance represents an important challenge in medicinal chemistry. This study aimed to design, synthesize, and biologically evaluate a series of novel morpholine-based nitrogen-rich heterocyclic hybrids as potential anticancer and antibacterial agents, supported by computational investigations. Methods: Twelve morpholine-derived nitrogen-enriched heterocyclic hybrids incorporating pyran, triazine, pyrimidinone, and sulfur-containing scaffolds were synthesized and fully characterized using IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. Their antiproliferative activities were evaluated against MCF-7 and HCT-116 cancer cell lines. The most active compounds were further investigated through kinase inhibition assays, cell cycle analysis, apoptosis, mitochondrial membrane potential, intracellular ROS determination, and apoptosis-related gene expression. Antibacterial, antibiofilm, antioxidant, and computational studies, including molecular docking, molecular dynamics simulations, MM-GBSA/MM-PBSA binding free-energy calculations, DFT calculations, and ADMET prediction, were also performed. Results: Compounds 3, 10, and 12 exhibited the highest antiproliferative activity, with compound 10 emerging as the lead candidate. It potently inhibited EGFR, PI3K, and mTOR, with IC50 values of 0.086 ± 0.003, 0.107 ± 0.005, and 0.223 ± 0.008 μM, respectively. Mechanistic investigations revealed G2/M arrest in MCF-7 cells and G0/G1 arrest in HCT-116 cells, accompanied by apoptosis rates of 32.66% and 37.12%; mitochondrial membrane depolarization; a 3.55-fold increase in intracellular ROS; upregulation of caspase-3, caspase-9, and Bax; and downregulation of Bcl-2, supporting activation of the intrinsic apoptotic pathway. Compound 10 also displayed the broadest antibacterial spectrum, surpassed ciprofloxacin against several tested isolates, exhibited MIC values of 5–20 μg/mL, achieved 42.80% inhibition of Pseudomonas aeruginosa biofilm formation, and showed the strongest antioxidant activity in DPPH and ABTS assays. Computational analyses supported the experimental findings by predicting stable interactions with EGFR and Staphylococcus aureus DNA gyrase, together with favorable MM-GBSA/MM-PBSA binding free energies of −23.44 and −24.99 ± 2.71 kcal/mol, respectively. Conclusions: The present findings identify compound 10 as a promising multifunctional lead with potent anticancer, antibacterial, antibiofilm, antioxidant, and multitarget kinase inhibitory activities. The combined biochemical, cellular, and computational findings support the proposed involvement of the EGFR/PI3K/mTOR signaling pathway in its antiproliferative activity and identify DNA gyrase as a potential antibacterial target. Nevertheless, the present study is limited to in vitro biological evaluation and computational investigations. Therefore, further in vivo efficacy studies, pharmacokinetic profiling, toxicity assessment, and experimental validation of the proposed molecular targets are warranted before considering preclinical development.
Hagar S. El-Hema, Esraa Adel, W. El-Dougdoug et al.· Pharmaceutics· 0 citations
Benzimidazole derivatives represent a versatile class of heterocyclic compounds with significant potential in
anticancer drug discovery. In the present study, a series of benzimidazole analogues was synthesized via the
modified Phillips condensation method and structurally characterized using FTIR, ¹H-NMR, ¹³C-NMR, mass
spectrometry, and elemental analysis. The synthesized derivatives were evaluated for cytotoxic activity against HL60 (acute promyelocytic leukemia) and K562 (chronic myelogenous leukemia) cell lines using the MTT assay, with
IC₅₀ values calculated through nonlinear regression analysis. Several compounds exhibited potent cytotoxic effects
in the low micromolar range, with halogen-substituted derivatives such as 2-chloro and 5-bromo analogues showing
IC₅₀ values below 6 μM. Selectivity indices confirmed preferential toxicity toward malignant cells compared to
normal peripheral blood mononuclear cells. Structure–activity relationship analysis revealed that electronwithdrawing substituents, extended π-conjugation, and para-position halogenation significantly enhanced biological
activity, while multiple hydroxyl substitutions reduced potency due to steric hindrance. Comparative evaluation with
standard drugs demonstrated that while doxorubicin exhibited higher potency, benzimidazole derivatives offered
better selectivity and broader applicability compared to imatinib. Statistical validation using ANOVA and logistic
dose–response models confirmed the robustness of experimental findings. These results underscore the potential of
benzimidazole derivatives as lead scaffolds for the development of novel antileukemic agents. Future directions
include in vivo validation, molecular docking, and ADMET predictions to refine pharmacological profiles and
facilitate clinical translation
N. Shilpika, A. Umayal, T. S. Amritha3 et al.· International Journal of Dru...· 0 citations