Isatin as a privileged scaffold for kinase inhibition: recent advances in anti-cancer research.

Indole-based derivatives as anticancer agents: recent advances in structure–activity relationships and biological mechanisms

Quinazoline-based VEGFR-2 Inhibitors: A Comprehensive Review of Design Strategies, SAR, and Therapeutic Advances.

INTRODUCTION Angiogenesis, primarily controlled by Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2), significantly influences tumor growth and metastasis. Consequently, VEGFR-2 targeting has emerged as an important strategy for cancer treatment. Owing to their known efficacy as strong tyrosine kinase inhibitors, quinazoline-based heterocycles have attracted considerable interest in medicinal chemistry. METHODS The pharmacophoric properties, Structure-Activity Relationship (SAR) insights, and therapeutic advancements of quinazoline-based VEGFR-2 inhibitors documented in recent literature were thoroughly examined in this review. RESULTS By interacting with the DFG motif (Aspartate-Phenylalanine-Glycine) and forming hydrogen bonds with essential hinge residues like Cys919, Glu885, and Asp1046, quinazoline scaffolds effectively inhibit VEGFR-2. According to SAR studies, the quinazoline core is essential for increasing potency and selectivity when coupled with urea or amide bonds and electron-withdrawing substituents. Derivatives with better inhibitory activity have been produced through recent structural changes, such as halogen substitutions and fused heterocycles. DISCUSSION AND CONCLUSION Quinazolines serve as efficient scaffolds for occupying hydrophobic subpockets within the VEGFR-2 active site, as discussed. These results highlight the clinical importance of quinazoline derivatives and imply that the development of hybrid analogues in the future has enormous potential to advance targeted cancer treatments.

Mechanism and Molecular Target of Substituted Triazoles: A Therapeutic Strategy in Anticancer Drug Discovery.

Cancer remains a leading cause of mortality worldwide, necessitating the continuous discovery and development of novel therapeutic agents with improved efficacy and reduced toxicity. Heterocyclic compounds are privileged scaffolds in medicinal chemistry, and among them, the triazole ring system (1,2,3-triazoles and 1,2,4-triazoles) has emerged as a highly versatile and promising pharmacophore for anti-cancer drug discovery. This review is an attempt to bridge the gap between synthetic structural biology and translational oncology by systematically connecting the structure- activity relationships of novel triazole hybrids targeting Aromatase, VEGFR-2, IDO1, and Carbonic Anhydrase. We present a comprehensive overview of the recent advancements in the design, structure-activity relationships, and biological evaluation of triazole derivatives as potent anticancer agents. Triazoles are known to play an important role in modulating key oncogenic pathways (such as apoptosis induction, cell cycle arrest, angiogenesis inhibition, and metastasis suppression) by binding to various pharmacological targets. Here, we critically present the spatial configuration, such as the "tail approach" needed for carbonic anhydrase inhibition and the very specific heme-iron distances of the IDO1 pathway that govern the therapeutic promise. Clinical progress, toxicity, bioavailability, and resistance challenges have also been addressed. This review underscores the significance of triazole derivatives as multifunctional anticancer agents and provides insights into future directions for their development as targeted and potent chemotherapeutic agents. Although triazole derivatives are widely recognized as versatile, drug-like moieties, a critical research gap persists in understanding minor structural or electronic modifications near the triazole ring system to make the molecule target-specific and prevent liabilities due to non-selectivity.

Chemical scaffolds, structure-activity relationships, and therapeutic potential of EphA2 small-molecule inhibitors.

EphA2 (ephrin type-A receptor 2) is a representative member of the Eph receptor tyrosine kinase family and is frequently overexpressed in a broad spectrum of malignant tumors. It participates in regulating tumor cell proliferation, migration, invasion, and angiogenesis through ligand-dependent and ligand-independent signaling pathways, thus emerging as a promising target for anticancer drug discovery. In recent years, extensive research has been carried out toward the discovery and optimization of small-molecule EphA2 inhibitors, covering a variety of chemical scaffolds with distinct mechanisms of action. This review provides a comprehensive overview of the research progress of EphA2-targeted small-molecule inhibitors reported to date. We systematically summarize their representative chemical scaffolds, structure-activity relationships, binding modes, and pharmacological profiles, and highlight the current challenges in selectivity, pharmacokinetic properties, and clinical translation. This review is expected to offer valuable guidance for the rational design and optimization of next-generation EphA2-targeted therapeutics.

Isatin Derivatives as Emerging Frontiers in Cancer Treatment: Recent Updates in Synthesis, Anticancer Effect, and SAR Studies

Due to its extensive biological activity and structural heterogeneity, the special nitrogen‐containing heterocyclic compound isatin (1 H ‐indole‐2,3‐dione) has attracted significant interest. This paper explains the synthesis and action of heterocyclic isatin hybrids that induce apoptosis by blocking kinases, serving as an appropriate model for the development of new anticancer drugs. Isatin has significant potential to form potent isatin hybrids and conjugates that target multiple carcinogenic pathways through various chemical modifications. Remarkably, isatin hybrids have demonstrated anticancer activity across numerous cancer cell lines. Their activities include inhibition of tubulin polymerization, caspase activation, apoptosis mediated by mitochondria, and regulation of kinases. Several synthetic isatin‐based drugs show excellent IC 50 values and low toxicity against normal cells. This review also summarizes recent synthetic advancements like microwave‐assisted and multi‐component methods. In addition to summarizing recent advances, this review critically integrates SAR, molecular docking, kinase selectivity, synthetic feasibility, CADD, predictive ADMET profiling, and translational challenges to afford a complete roadmap for isatin‐based anticancer drug discovery. Overall, these findings reveal that isatin is a useful framework for developing new anticancer drugs. In the future, nano‐formulation drug delivery systems with new drug signaling pathways will be promoted to increase bioavailability and targeted delivery, especially in solid tumors.

Molecular Optimization of Benzimidazole Scaffolds for Targeted Protein Kinase Inhibition in Oncology

Benzimidazole is one of the most prestigious heterocyclic motifs, with a variety of biological applications. Over the years, diverse benzimidazole hybrids have proved single or multi‐protein kinase inhibitory activity. Some examples were approved by the Food and Drug Administration (FDA) for use in the treatment regimens of certain types of cancers, other benzimidazole‐based protein kinase inhibitors are still in clinical trials. Additionally, different research groups have employed different approaches for the design of novel benzimidazole hybrids targeting protein kinases in oncology. In the current review article, a comprehensive overview is provided on the incorporation of the benzimidazole scaffold in FDA‐approved drugs, as well as in clinical trial candidates being developed as protein kinase inhibitors for cancer treatment. Additionally, recent advances in rational design strategies, molecular modeling, protein kinase inhibition, antiproliferative activity, and structure–activity relationships (SAR) of novel benzimidazole‐based hybrids targeting single or multiple kinases are summarized.