Quinoline- and Quinolone-Based Compounds: A Systematic Review of Structure–Activity Relationships, Pharmacological Activities, and Resistance Mechanisms

Background: Quinoline- and quinolone-based compounds are important heterocyclic scaffolds investigated for diverse pharmacological applications. However, their structure–activity relationships (SARs), pharmacological profiles, and associated resistance mechanisms remain widely dispersed across the literature. Methods: A systematic review was conducted and reported in accordance with the PRISMA 2020 guidelines. Google Scholar, Google Patents, PubMed, Scopus, and Web of Science were searched for English-language, peer-reviewed articles published from 1 January 2020 to 29 August 2026. Original research articles with full texts available and compound-specific pharmacological, SAR, mechanistic, or resistance data were included. Of 312 identified records, 248 remained after duplicate removal; of these, 130 full-text articles were assessed, of which 34 were excluded, leaving 96 included studies. Results: The included studies investigated quinoline and quinolone derivatives for anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, neurological and neuroprotective, cardiovascular and neurovascular, antimalarial and other antiprotozoal, antitubercular, and enzyme-inhibitory activities. Compound (60e) exhibited MICs of 0.5, 1, and 2 μg/mL against H37Rv, multidrug-resistant, and extensively drug-resistant Mycobacterium tuberculosis, respectively. Compound (162) retained an MIC of 0.125 μg/mL against three levofloxacin-resistant MRSA isolates, whereas levofloxacin showed MICs > 64 μg/mL. Compounds (130a) and (130b) showed potent antiplasmodial activity against chloroquine-resistant Plasmodium falciparum FcB1, with IC50 values of 1.5 and 1.9 nM, respectively. Antiviral investigations identified quinolinone derivatives targeting HIV-1 integrase and the RNase H function of reverse transcriptase, alongside quinoline-based inhibitors of SARS-CoV-2 papain-like and main proteases. For antibacterial quinolones, resistance mechanisms included mutations in the quinolone resistance-determining regions of GyrA and ParC, plasmid-mediated quinolone resistance genes, and efflux pumps. Conclusions: Scaffold modifications, molecular hybridization, and functionalization at N-1, C-2, C-3, C-6, C-7, and C-8 were associated with changes in pharmacological activity and potency, depending on the scaffold, biological target, and assay system. These findings highlight the versatility of quinoline and quinolone scaffolds for pharmacological optimization and underscore the importance of understanding the structural determinants of activity and resistance.