Indolizidine, Antiinfective and Antiparasitic Compounds from Prosopis glandulosa var. glandulosa

A new potent antiinfective and antiparasitic 2,3-dihydro-1H-indolizinium chloride (1) was isolated from Prosopis glandulosa 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. Structures were determined by 1D and 2D NMR and mass spectra. Compound 1 showed potent in vitro antifungal activity against Cryptococcus neoformans and Aspergillus fumigatus (IC50 values = 0.4 and 3.0 mu g/mL, respectively) and antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare (IC50 values of 0.35 and 0.9 mu g/mL, respectively). The remarkable in vitro fungicidal activity of 1-4 against C neoformans (MFCs = 0.63-1.25 mu g/mL) and 2, 3, and 5 against A. fumigatus (MFCs = 0.63-2.5 mu g/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 similar to 76% of C neoformans infection from brain tissue compared to similar 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 (chloroquine, IC50 = 17 and 140 ng/mL). Prosopilosine (1) also showed in vivo antimalarial activity, with an ED50 value of similar to 2 mg/kg/day/ip against Plasmodium berghei-infected mice after 3 days of treatment.