Quinolones have recently gained significant interest in oncology due to their structural versatility and broad pharmacological potential. Their modifiable scaffold makes them attractive candidates for anticancer drug development, enabling optimization of potency, selectivity, and pharmacokinetic properties. This review highlights recent advances in the synthesis of 2-quinolone and 4-quinolone derivatives, with an emphasis on emerging strategies such as metal-catalyzed reactions, photochemical approaches, base-mediated transformations, and metal-free methodologies. We summarize contemporary structure-activity relationship (SAR) studies that elucidate features governing anticancer activity in quinolone-based compounds. Additionally, we discuss mechanistic evidence demonstrating that quinolones exert antitumor effects through diverse molecular pathways, including topoisomerase inhibition, apoptosis induction, cell-cycle arrest, G-quadruplex stabilization, HDAC inhibition, modulation of miRNA processing, and regulation of key oncogenic signaling networks such as EGFR/PI3K/mTOR and S1P. The current landscape of quinolone-derived anticancer agents in preclinical and clinical development is also reviewed. Overall, this article provides a comprehensive and translational perspective on the synthetic advances, SAR insights, and mechanistic foundations supporting the development of 2- and 4-quinolone scaffolds as promising anticancer therapeutics.

Since its approval for clinical use more than two decades ago, memantine has become a blockbuster drug against Alzheimer's disease (AD). Unlike other FDA approved small molecules for the treatment of AD, essentially acetyl cholinesterase inhibitors, memantine behaves as N-methyl-d-aspartate (NMDA) receptor antagonist. However, it is a weak and non-specific NMDA receptor channel blocker that has shown to be safe in slowing the decline of moderate to advanced AD symptoms. In fact, those of us familiarized with AD, are aware of clinical protocols where memantine is usually prescribed to mitigate late stages of this neurological disorder, following previous treatment with donepezil and other inhibitors. The role of memantine for either preventing or disrupting amyloid formation, yet promising, remains unconclusive. The pharmacological basis and mode of action of memantine are well known and have been reviewed from different standpoints, often within the context of adamantane scaffolds. In recent times, further analyses combining experiment and computational simulation have disclosed subtle features of memantine-receptor interactions and previously unrecognized mechanistic insights, which are summarized herein. Likewise, there is a growing interest in memantine derivatives, not only against neurodegeneration, but also versus unrelated pathologies. Such studies arising from lab observations and preclinical assessments at most, point to memantine's repurposing and open the door to further explorations and translation. It is noteworthy that some structural aspects of memantine, including crystal packing and polymorphism, are usually overlooked. This review pays attention to such key elements and updates synthetic protocols, including the first preparation of memantine in continuous flow.

Viral proteases are central targets in antiviral drug discovery and development because they play essential roles in viral replication and maturation. Although protease inhibitors have achieved major clinical success, traditional design strategies face challenges, including resistance development, poor oral exposure of early peptidomimetics, and off-target toxicity of highly reactive covalent warheads. Classical approaches, such as peptidomimetics, macrocyclization, and covalent warhead engineering, are discussed alongside contemporary strategies, including allosteric modulation and targeted protease degradation via proteolysis-targeting chimeras (PROTAC) technology. Particular emphasis is placed on how these strategies address key obstacles, such as resistance evolution, selectivity, metabolic stability, and oral bioavailability. Several quantitative case studies have also demonstrated the growing significance of computational tools in contemporary antiviral discovery. For SARS-CoV-2 main protease (Mpro), these workflows were enabled by the rapid availability of high-resolution experimental crystal structures of the target protein. The evolution of a weak fragment (Kd ≈ 1.7 mM; ΔG ≈ -3.6 kcal/mol) into a covalent inhibitor (QUB-00006-Int-07) with enzymatic inhibition (IC50 ≈ 830 nM) was successfully guided by molecular dynamics (MD) simulations and absolute binding free energy calculations. This was subsequently confirmed experimentally using NMR, ESI-MS, and FRET assays. Furthermore, out of 25 computationally prioritized candidates with Ki values less than 4 μM, 15 active Mpro inhibitors were identified using accelerated free-energy perturbation-based repurposing campaigns. Long-range allosteric pathways connecting the catalytic site to resistance-associated regions and experimentally verified allosteric pockets have also been discovered using dynamic nonequilibrium MD. Together, these integrated in silico approaches enable the early prioritization of high-affinity ligands, mechanistic understanding of resistance, and significant reduction of late-stage attrition in antiviral drug discovery. Through detailed case studies on SARS-CoV-2 main protease (Mpro), Zika virus NS2B-NS3 protease, and Dengue virus NS2B-NS3 protease, the review illustrates how medicinal chemistry principles translate molecular insights into clinically relevant antivirals. Finally, a forward-looking development roadmap is proposed that integrates potency, selectivity, pharmacokinetics, manufacturability, and resistance management toward the goal of broad-spectrum, durable, and adaptable protease-targeted therapeutics development.