Due to emerging drug resistance, antimalarial drugs are losing their effectiveness. This underscores the need to develop novel antimalarial compounds with mechanisms of action distinct from those currently in use. Previous work has identified a 4-nitrostyryl quinoline compound (UCF 501) with excellent selectivity, submicromolar antimalarial activity, and a mechanism of action distinct from current antimalarials. UCF 501 does not inhibit β-hematin formation like other quinoline derivatives currently in use, such as chloroquine and amodiaquine. Furthermore, UCF 501 acts quickly during all stages of the intraerythrocytic lifecycle, and, unlike other approved antimalarial drugs, inhibits merozoite formation. Current work is focused on the hit-to-lead optimization of UCF 501. We replaced the chiral amine moiety with 3-morpholinopropylamine and 3-dimethylaminopropylamine at the quinoline 4 position and conducted SAR on the resulting compounds to assess the structural requirement for a chiral amine. This produced compounds with activity profiles better than that of UCF 501, indicating that a chiral center on the amino group was not necessary for antiplasmodial activity. We also assessed the effects of substituents on the styryl aromatic ring. Phenyl, 4-fluorophenyl, 4-trifluorophenyl, and 4-methoxycarbaldehyde were substituted for the styryl 4-nitrophenyl. The resulting analogues all showed submicromolar antimalarial activity, but the nitro group analogs were still the most potent. Further optimization efforts will focus on reducing potential cytotoxicity of the nitro group. This will be done by screening the regioisomers of the 4-nitrostyryl group (<i>m</i>-nitrophenyl, <i>p</i>-nitrophenyl) to determine role the nitro group plays in the binding process. Isosteres of the nitro group, such as pyridyls, difluorophenyls, sulfone, and sulfonamide, will be screened to identify analogs with increased potency and reduced cytotoxicity.

Styrylquinoline: A scaffold for the next generation of antimalarials

255th National Meeting (2018)

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