Indolizidine, Antiinfective and Antiparasitic Compounds from Prosopis glandulosa Torr. Var. glandulosa

A new potent antiinfective and antiparasitic 2,3-dihydro-1H-indolizinium chloride, (1), was isolated from Prosopis glandulosa Torr. var. glandulosa. Three additional new (2–4) and one known (5) indolizidines were also isolated, and the dihydrochloride salts of 1–3 (compounds 6, 7 and 8) were prepared. The structures were determined by 1D and 2D NMR and mass spectra. Compound 1 showed potent in vitro antifungal and antibacterial activities against Cryptococcus neoformans, Aspergillus fumigatus, methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare. The remarkable fungicidal activity of 1–4 against C. neoformans and 2, 3, and 5 against A. fumigatus were similar to amphotericin B, but > 2–4-fold more potent than 6–8. Prosopilosidine (1) showed potent in vivo activity at 0.0625 mg/Kg/day/ip for 5 days in a murine model of cryptococcosis by eliminating ~ 76% of C. neoformans infection from brain tissue compared to ~ 83% with amphotericin B at 1.5 mg/Kg/day. Compounds 1 and 4 exhibited potent activity against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum. Prosopilosine (1) also showed in vivo antimalarial activity with an ED₅₀ value of ~ 2 mg/Kg/day/ip against Plasmodium berghei-infected mice after 3 days of treatment.

Acknowledgements: The authors sincerely thank Dr. Alice M. Clark, Vice-Chancellor for Research and sponsored programs, UM, for her valuable advise on antifungal activity of compounds, and Dr. Troy Smillie, Dr. D. Chuck Dunbar, Ms. Sharon Sanders, Mr. John Trott, Ms. Marsha Wright, Dr. Anupam Pradhan, Ms. Lavanya Madgula and Mr. Mohammed A. Hammad, NCNPR, for plant acquisition and biological work. This work was supported in part by the USDA-ARS Specific Cooperative Agreement No. 58-6408-2-0009, NIH, NIAID, Division of AIDS, Grant No. AI 27094, and MMV Grant No. 06-2026.