Quinolones represent one of the largest classes of synthetic antibiotics used in both human and veterinary medicine. Since the discovery of nalidixic acid, a substantial body of research has been carried out on quinolones, resulting in the synthesis of several quinolone derivatives with exceptional pharmacology. In addition to their antibacterial action, quinolones have a broad spectrum of diverse biological activities. In this regard, the present review examines the literature of recent years describing synthesis protocols, reactivity and biological properties, with particular emphasis on the antibacterial, antimalarial, antitrypanosomal, antileishmanial, antiviral and anticancer activities of this famous class of molecules. Finally, this review highlights the potential of quinolones as preferred pharmacophores in medicinal chemistry. The aim is to highlight the innovative aspects of the rational design of new therapeutic agents with this structural motif, in the face of emerging antibiotic resistance and the urgent need for new active molecules.

Quinolones represent one of the largest classes of synthetic antibiotics used in both human and veterinary medicine. Subsequent to the discovery of nalidixic acid, a substantial body of research has been carried out on quinolones, resulting in the synthesis of a number of quinolone derivatives with exceptional pharmacology. In addition to their antibacterial action, quinolones have a broad spectrum of diverse biological activities. In this regard, the present review examines the literature of recent years describing synthesis protocols, reactivity and biological properties, with particular emphasis on the antibacterial, antimalarial, antitrypanosomal, antileishmanial, antiviral and anticancer activities of these famous nuclei. Finally, this review highlights the potential of quinolones as preferred pharmacophores in medicinal chemistry. The aim is to highlight the innovative aspects of rationally designing new therapeutic agents with this structural motif, in the face of emerging antibiotic resistance and the urgent need for new active molecules.

Background/Objectives: The rise in antibiotic resistance presents a serious and urgent global health challenge, emphasizing the need to develop new therapeutic compounds. This study focuses on the design and evaluation of a novel series of hybrid molecules that combine the 2-quinolone and 1,2,3-triazole pharmacophores, both recognized for their broad-spectrum antimicrobial properties. Methods: A library of 29 candidate molecules was first designed using in silico techniques, including QSAR modeling, ADMET prediction, molecular docking, and molecular dynamics simulations, to optimize antibacterial activity and drug-like properties. The most promising compounds were then synthesized and characterized by ¹H and ¹³C NMR APT, mass spectrometry (MS), Fourier-transform infrared (FT-IR) spectroscopy, and UV-Vis spectroscopy. Results: Antibacterial evaluation revealed potent activity against both Gram-positive and Gram-negative bacterial strains, with minimum inhibitory concentration (MIC) values ranging from 0.019 to 1.25 mg/mL. Conclusions: These findings demonstrate the strong potential of 2-quinolone–triazole hybrids as effective antibacterial agents and provide a solid foundation for the development of next-generation antibiotics to combat the growing threat of bacterial resistance.

Quinoline is a bicyclic aromatic heterocycle composed of a fused benzene and pyridine ring, and it has held an important place in medicinal chemistry for nearly two centuries. F. Runge first isolated it from coal tar in 1834, and it was later found to form the structural core of well-known natural products such as quinine, camptothecin, and γ-fagarine. Its asymmetric electron distribution, amphoteric character, and ability to undergo both electrophilic and nucleophilic substitution confer considerable pharmacophoric versatility on the quinoline scaffold. This review covers the chemistry and therapeutic relevance of quinoline derivatives, with an emphasis on their pharmacological significance rather than on their synthesis alone. It begins with a brief account of the scaffold’s structural features and main synthetic routes, then examines the biological activities reported for quinoline-based compounds, including antibacterial, anticancer, anti-inflammatory, antimalarial, antiparasitic, antitubercular, antioxidant, and antiviral activities, together with structure–activity relationships discussed at the level of specific ligand–target interactions where data allow. The last section covers more recent directions in quinoline-based drug discovery, including PROTAC degraders, kinase inhibitors, and multitarget-directed ligands, an area not extensively addressed in earlier reviews of this scaffold. The literature surveyed here shows that quinoline derivatives continue to serve as a versatile scaffold for generating new leads, linking established synthetic chemistry with current mechanistic and computational approaches. The continued diversification of quinoline-based chemotypes and their biological mechanisms reinforces the importance of this scaffold as a versatile platform for medicinal chemistry and drug discovery.

Nine N-alkylated phenytoin derivatives (5-13) have been synthesized and characterized using spectroscopic tools with the structures of 4-6 confirmed by X-ray crystallography. The starting material, phenytoin 2, was obtained by a base-catalyzed condensation from benzyl and urea. Its alkylation with benzyl chloride yields 3 and 4. Subsequently, the alkylation of 3 with various alkyl halides under solid-liquid phase transfer catalysis (PTC) led to the formation of 5-13. The intercontacts in 4-6 crystals are identified by analyzing their corresponding Hirshfeld surfaces and fingerprint plots, and the HS analysis reveals that the most intercontacts involved H^…H interactions. DFT calculations relatively well reproduce X-ray geometrical parameters in IEF-PCM at the B3LYP/6-3111++G(d,p) level of theory. The calculated electronic and molecular properties demonstrate that the N-alkylation of 5-6 may have slight effects on the calculated, and that reactivity is relatively similar. The inhibitory potency of 4-6 towards cholesterol oxidase (ChOx) is estimated by investigating their binding affinity into the binding site of binding cholesterol oxidase. The compound 4 with N-benzyl moiety displays higher binding affinity than 5 and 6 with N-methyl and N-ethyl moieties. Additionally, the stability of 4 in the binding site ChOx was evaluated and an 80 ns MD simulation was conducted. MD analysis shows that the 4-ChOx complex remained stable throughout the simulation, showing minimal conformational changes, which confirms the stability of 4 in the ChOx binding site.