Synthetic quinolone-tethered aminoguanidine derivatives exhibit potent anti-plasmodial activity

Synthetic quinolone-tethered aminoguanidines were studied in our continuous efforts to develop innovative therapies against malaria.

Twenty-three quinolone-tethered aminoguanidines were evaluated for in vitro antiplasmodial activity against chloroquine-sensitive Plasmodium falciparum 3D7 using the SYBR Green I fluorescence assay. Selected compounds with high selectivity indices were further tested against multidrug-resistant K1 and Dd2 strains. Cytotoxicity was assessed to determine selectivity indices. The top hit compounds were examined for stage-specific effects on asexual blood-stage parasite development and potential cidal activity upon prolonged incubation. In silico analyses were performed to predict possible protein targets, and in vivo efficacy was evaluated in P. yoelii 17XNL-infected mice using parasitaemia and area under the curve (AUC) analysis.

All 23 tested compounds potently inhibited P. falciparum proliferation in vitro, with IC₅₀ values ranging from 0.58 to 18.29 µM for the chloroquine-sensitive strain 3D7. Five compounds (1, 7, 9, 13, and 17) with the highest selectivity indices (SI >25) also maintained activity against P. falciparum K1 and Dd2, with IC₅₀ values ranging from 0.74 to 5.11 µM and 0.92-8.02 µM, respectively. The top two hit compounds, 1 and 7, with IC₅₀ <1.5 µM, low cytotoxicity (CC₅₀ >40 µM), and SI >40, were further examined and found to arrest asexual blood-stage parasite development at the ring, trophozoite, and schizont stages, also exhibited potential cidal effects upon prolonged incubation. An in silico study predicted that these compounds may target P. falciparum heat shock protein 90 (HSP90), cyclin-dependent kinase-2 homolog (CDK2H), and bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS), suggesting a multi-target mechanism of action. In vivo evaluation in P. yoelii 17XNL-infected mice demonstrated that Compounds 1 and 7 significantly suppressed parasitaemia compared with the vehicle control. Quantitative analysis based on the area under curve (AUC) showed reductions of 39.2% and 41.1% for Compounds 1 and 7 at 10 mg/kg, respectively. At 20 mg/kg, stronger inhibition was observed, with AUC reductions of 50.6% and 53.9%, respectively, relative to the control group.

These results highlight quinolone-tethered aminoguanidine analogues as promising antimalarial candidates and potential for further development.