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 (IC(50) values = 0.4 and 3.0 microg/mL, respectively) and antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare (IC(50) values of 0.35 and 0.9 microg/mL, respectively). The remarkable in vitro fungicidal activity of 1-4 against C. neoformans (MFCs = 0.63-1.25 microg/mL) and 2, 3, and 5 against A. fumigatus (MFCs = 0.63-2.5 microg/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 approximately 76% of C. neoformans infection from brain tissue compared to approximately 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 approximately 2 mg/kg/day/ip against Plasmodium berghei-infected mice after 3 days of treatment.
Samoylenko
Volodymyr
V
National Center for Natural Products Research and Department of Pharmacology, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
Ashfaq
Mohammad K
MK
Jacob
Melissa R
MR
Tekwani
Babu L
BL
Khan
Shabana I
SI
Manly
Susan P
SP
Joshi
Vaishali C
VC
Walker
Larry A
LA
Muhammad
Ilias
I
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000977:Antiparasitic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D003455:Cryptococcus neoformans / Q000187:drug effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D054836:Indolizidines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009505:Nevada; D010946:Plants, Medicinal / Q000737:chemistry*; D010962:Plasmodium berghei / Q000187:drug effects; D029862:Prosopis / Q000737:chemistry*
D000890:Anti-Infective Agents; D000977:Antiparasitic Agents; D054836:Indolizidines; D002738:Chloroquine