Medicinal Chemistry Perspective of 1,8-Naphthyridines as Anticancer Agents

Cancer remains a leading cause of death worldwide, mainly due to chemo resistance and the limited chemotherapy options. 1,8-Naphthyridine (NP) is a promising scaffold in medicinal chemistry, recognized for its wide range of biological activities, including anticancer, anti-inflammatory, antimalarial, antibacterial, antiprotozoal, anti-mycobacterial, and antiplatelet effects. In addition, these synthetic derivatives have been shown to exhibit a wide range of activities, including anti-osteoporotic (α(v)β(3) antagonists), antioxidant, epidermal growth factor receptor (EGFR) inhibition, protein kinase inhibition, ionotropic effects, β-3 antagonism, anti-allergic, antimalarial, gastric anti-secretory, bronchodilator, anticonvulsant, anti-hypertensive, platelet aggregation inhibition, MDR modulation, adenosine receptor agonist, adrenoceptor antagonist, and pesticide activities. In this review, we attempt to compile and discuss various approaches (Vilsmeier-Haack reaction, Conrad-Limpach reaction, double hetero-annulation process of Michael abducts, the Friedlander synthetic approach) for the synthesis of NPs and the anticancer effect of these derivatives on different targets, including receptor tyrosine kinases (such as EGFR, fibroblast growth factor receptors), casein kinase 2, c-Met kinase, DNA topoisomerase, cannabinoid, and phosphoinositide-dependent kinase 1 (PDK1) receptors with their associated signaling pathways, mechanisms of action, and the structure-activity relationship (SAR). This review offers an in-depth medicinal and pharmacological profile of NPs as anticancer agents, intending to guide researchers in developing novel, selective, effective, and safe anticancer agents.