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

Abstract

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. 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 (IC 50 values = 0.4 and 3.0 μg/mL, respectively), and antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare (IC 50 values of 0.35 and 0.9 μg/mL, respectively). The remarkable in vitro fungicidal activity of 1-4 against C. neoformans (MFCs = 0.63→1.25 μg/mL) and 2, 3, and 5 against A. fumigatus (MFCs = 0.63→2.5 μg/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 IC 50 values of 39 and 95 ng/mL, and 42 and 120 ng/mL, respectively; (chloroquine, IC 50 = 17 and 140 ng/mL). Prosopilosine (1) also showed in vivo antimalarial activity with an ED 50 value of ~2 mg/Kg/day/ip against Plasmodium bergheiinfected mice after 3 days of treatment.Plants of the genus Prosopis are trees or shrubs distributed in arid and semiarid tropical and subtropical regions. P. glandulosa Torrey var. glandulosa (Leguminosae), a medium-sized * To whom correspondence should be addressed. Tel. (662) Decoctions of leaves and pods are generally used to make eye washes to treat pink eye. 5 An ethanolic extract of P. glandulosa from Pakistan yielded triterpenes, flavonoids, glycosides and the indolizidine alkaloid juliprosopine. [6][7][8][9][10] Among the indolizidines reported from Prosopis species to date, 6-11 the stereochemistry of juliprosine and juliprosopine were established by chemical synthesis. 12 The piperidinyl indolizidines, such as juliprosopine, and their analogs exhibited in vitro antibmicrobial, antidermatophytic, pesticidal, and amebicidal activities. 11,[13][14][15][16][17][18][19][20] In addition, their toxicity, 20-22 DNA binding activity 23 , inhibitory effects on β-glucosidase enzymes 23 and plant growth inhibitory activities were also reported. 10,24 This paper describes the isolation of the new potent antifungal and antimalarial dihydroindolizinium chloride prosopilosidine (1) from honey mesquite, together with three new analogs prosopilosine (2), isoprosopilosine (3) and isoprosopilosidine (4), and the known juliprosopine (5). 25,26 P. glandulosa Torrey var. glandulosa, has not previously been subjected to chemical or biological investigations. Prosop...

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