Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2008
Publication Date: 1/23/2009
Citation: Samoylenko, V., Ashfaq, M.K., Jacob, M.R., Tekwani, B.L., Khan, S.I., Manly, S.P., Joshi, V.C., Walker, L.A., Muhammad, I. 2009. Indolizidine, Antiinfective and Antiparasitic Compounds from Prosopis glandulosa var. glandulosa. Journal of Natural Products. 72(1):92-98. Interpretive Summary: Four new indolizidine alkaloids prosopilosidine (1), prosopilosine (2), isoprosopilosine (3) and isoprosopilosidine (4), and the known juliprosopine (5), were isolated from Prosopis glandulosa Torr. var. glandulosa. Their structures were determined by 1D and 2D NMR spectra. The in vitro fungicidal activity of 1-4 against C. neoformans and 2, 3 and 5 against A. fumigatus were similar to amphotericin B. Compounds 1 and 4 also exhibited potent activity against chloroquine-sensitive (D6) and -resistant (W2) strains of Plasmodium falciparum. This paper also reports the in vivo activity of 1 against C. neoformans and antimalarial activity against P. bergheii.
Technical Abstract: Prosopilosidine, a new potent antiinfective and antiparasitic 2,3-dihydro-1H-indolizinium chloride, (1), was isolated from Prosopis glandulosa Torr. var. glandulosa. Furthermore, three additional new and one known indolizidines, prosopilosine (2), isoprosopilosine (3), isoprosopilosidine (4) and juliprosopine (5), were isolated, and the dihydrochloride salts of 1-3 (compounds 6, 7 and 8) were prepared. Their structures were determined by 1D and 2D NMR spectra, including COSY, HMQC, HMBC and NOESY spectra. Compound 1 showed potent in vitro antifungal activity against Cryptococcus neoformans and Aspergillus fumigatus (IC50 values = 0.4 and 3.0 ug/mL, respectively), and antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare (IC50 values of 0.35 and 0.9 ug/mL, respectively). The remarkable in vitro fungicidal activity of 1-4 against C. neoformans (MFCs = 0.63-1.25 ug/mL) and 2, 3, and 5 against A. fumigatus (MFCs = 0.63-2.5 ug/mL) 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 and high selectivity index (SI) values against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum with IC50 values of 39 and 95 ng/mL, and 42 and 120 ng/mL, respectively, which was equipotent to the chloroquine (IC50 = 17 and 140 ng/mL). 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, suggesting indolizidine as a novel antimalarial pharmacophore.