In Vivo Efficacy and Metabolism of the Antimalarial Cycleanine and Improved In Vitro Antiplasmodial Activity of Semisynthetic Analogues.

Bisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the in vitro antiplasmodial activity of three BBIQ alkaloids (cycleanine [compound 1], isochondodendrine [compound 2], and 2'-norcocsuline [compound 3]) isolated from the Triclisia subcordata Oliv. medicinal plant traditionally used for the treatment of malaria in Nigeria are studied alongside two semisynthetic analogues (compounds 4 and 5) of cycleanine. The antiproliferative effects against a chloroquine-resistant Plasmodium falciparum strain were determined using a SYBR green 1 fluorescence assay. The in vivo antimalarial activity of cycleanine is then investigated in suppressive, prophylactic, and curative murine malaria models after infection with a chloroquine-sensitive Plasmodium berghei strain. BBIQ alkaloids (compounds 1 to 5) exerted in vitro antiplasmodial activities with 50% inhibitory concentration (IC50) at low micromolar concentrations and the two semisynthetic cycleanine analogues showed an improved potency and selectivity compared to those of cycleanine. At oral doses of 25 and 50 mg/kg body weight of infected mice, cycleanine suppressed the levels of parasitemia and increased mean survival times significantly compared to those of the control groups. The metabolites and metabolic pathways of cycleanine were also studied using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Twelve novel metabolites were detected in rats after intragastric administration of cycleanine. The metabolic pathways of cycleanine were demonstrated to involve hydroxylation, dehydrogenation, and demethylation. Overall, these in vitro and in vivo results provide a basis for the future evaluation of cycleanine and its analogues as leads for further development.

Coupling Plant-Derived Cyclotides to Metal Surfaces: An Antibacterial and Antibiofilm Study.

Modification of metal surfaces with antimicrobial peptides is a promising approach to reduce bacterial adhesion. Here, cyclic peptides or cycloids, possessing remarkable stability and antimicrobial activities, were extracted and purified from Viola philippica Cav., and identified using mass spectrometry. Cyclotides were subsequently utilized to modify stainless steel surfaces via polydopamine-mediated coupling. The resulting cyclotide-modified surfaces were characterized by Fourier transform infrared (FTIR) spectroscopy and contact angle analysis. The antibacterial capacity of these cyclotides against Staphylococcus aureus was assessed by Alamar blue assay. The antibiofilm capacity of the modified surfaces was assessed by crystal violet assay, and scanning electron microscopy (SEM). A composite of Kalata b1, Varv A, Viba 15 and Viba 17 (P1); Varv E (P2); and Viphi G (P3) were isolated and identified. FTIR analysis of the modified surfaces demonstrated that cyclotides bound to the surfaces and induced reduction of contact angles. Antimicrobial effects showed an order P3 > P1 and P2, with P3-treated surfaces demonstrating the strongest antibiofilm capacity. SEM confirmed reduced biofilm formation for P3-treated surfaces. This study provides novel evidence for cyclotides as a new class for development of antibacterial and antibiofilm agents.

Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cells.

Our previous studies demonstrated that cycleanine, a macrocyclic bisbenzylisoquinoline (BBIQ) alkaloid, showed potent anti-ovarian cancer activity via apoptosis induction. Here, we synthesized two novel (aminoalkyl)cycleanine analogues (2 and 3) through a simple and efficient two-step reaction starting from cycleanine isolated from Triclisia subcordata Oliv. These analogues showed greater potency than the unmodified cycleanine in three human ovarian cancer cell lines. Both 2 and 3 induced apoptosis in ovarian cancer cells by activations of caspases 3/7, cleavage of PARP, increase in subG1 cell cycle phase and in the percentage of apoptotic cells. Further confocal fluorescence microscopy analysis confirmed the cellular uptake of alkaloids in ovarian cancer cells by using the unique (alkynyl)cycleanine (3) via click chemistry reaction. Our results suggest that cycleanine could be a hit compound for the future development in attacking ovarian cancer.

Antinociceptive and anti-inflammatory activities of crude extracts of Ipomoea involucrata leaves in mice and rats

OBJECTIVE@#To investigate antinociceptive and anti-inflammatory activities of crude extract from Ipomoea involucrata leaves (Convolvulaceae) in mice and rats.@*METHODS@#The antinociceptive activity was tested using acetic acid-induced abdominal writhing test in mice. The anti-inflammatory activity was evaluated using egg albumin induced oedema of rat paw.@*RESULTS@#Phytochemical screening showed the presence of alkaloids, flavonoids, saponins, terpenoids and tannin. At the doses of 25-100 mg/kg, Ipomoea involucrata exhibited dose-dependent and significant increase in pain threshold in acetic acid -induced writhing test of mice (P<0.05, student t-test) The administration of Ipomoea involucrata leaf extract (25-100 mg/kg) showed dose-dependent decreases in paw volume of egg albumin induced oedema in rats and a significant higher anti-inflammatory activity compared to the standard control (Aspirin).@*CONCLUSIONS@#These results support the claims on the traditional use of the of Ipomoea involucrata leaves in the treatment of toothache, rheumatic pains and other inflammatory conditions. Studies on the isolation and structural elucidation of the active principle are still needed being carried out.