SAR Studies and Rational Semisynthetic Modifications of Manzamine A for Anti-Malarial Activity

Malaria is a serious infectious disease causing high annual mortality rates, in particular due to growing in international tourism to infected areas. Manzamine A, is the first representative of the manzamine alkaloids and bears a unique multi-heterocyclic ring system attached to a β-carboline moiety. Manzamine A shows potent activity as an antimalarial agent however its toxicity reduces its potential as a drug candidate. Quaternary carbolinium salts have been shown to have better antimalarial activity and less cytotoxicity than electronically neutral β-carbolines [1]. Quaternary carbolinium salts of manzamine A were synthesized and evaluated for their antiplasmodial activity. Methylation of manzamine A was performed using methyl trifluoromethanesulfonate in two different molar ratios to afford 2-N-methylmanzamine A (1) and 2-N,12-O-dimethylmanzamine A (2). The structures of 1 and 2 were established utilizing high resolution ESI-MS, 1H-NMR, 13C-NMR and HMBC, HMQC. Resulting bioactivity data showed that 1 and 2 had low cytotoxicity in Vero cells (> 8237.8 µM) compared to manzamine A (IC₅₀ = 364.5 µM) and however both analogs 1 and 2 were less potent (IC₅₀ = 319.3 and 1557.6 µM respectively) than manzamine A (IC₅₀ = 8.2 µM) against Plasmodium falciparum. Acknowledgements: This work was supported by the Public Health Service, grant number R29 AI 36596-01A1 from the National Institute of Allergy and Infectious Diseases, and, in part, by the Center for Disease Control, Cooperative Agreement No. U50/CCU418839 (M.A.A.). Anti-malarial assays were conducted by John Trott. Additional support through the Ministry of Scientific Research and Higher Education – Egypt. References: [1] Takasu K, et al. (2004) Bioorganic & Medicinal Chemistry Letters 14: 1689–1692.