New Polyfunctional Phragmalin Limonoids from Neobeguea mahafalensis.

Neobeguea mahafalensis is used as a medicinal plant in Madagascar. A decoction of the stem bark of this species is reported to treat back pain. Recently, it was reported that a decoction of the root bark, containing two novel phragmalin limonoids as identified active constituents, exhibited an extraordinarily high potency and remarkably long duration in augmenting sexual activity in male rodents.

Semisynthesis of libiguin A and its analogues by trans-lactonization of phragmalin.

Libiguins are limonoids with highly potent sexual activity enhancing effects, originally isolated from the Madagascarian Meliaceae species Neobeguea mahafalensis, where they exist in only minute quantities. Their low natural abundance has hampered mapping of their biological effects. Here we describe an approach to the semisynthesis of libiguin A and its close analogues 1-3 starting from phragmalin, which is a limonoid present in high amounts in a commercially cultivated Meliaceae species, Chukrasia tabularis, allowing the preparation of libiguins in appreciable quantities.

Libiguins A and B: novel phragmalin limonoids isolated from Neobeguea mahafalensis causing profound enhancement of sexual activity.

In a screening programme directed towards the discovery of drugs that could enhance sexual activity, we found that a decoction of the root bark of Neobeguea mahafalensis displayed an extraordinarily high potency and remarkably long duration in augmenting sexual activity in male rodents. Bioassay-guided fractionation led to the isolation of two pharmacoactive constituents, which turned out to be novel 1,8,9-orthoacetate phragmalin limonoids that we named libiguins A and B, each with a C-16/30 δ-lactone ring. Chemical structures were established by the interpretation of their 1D and 2D NMR data.

Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases.

A series of 45 peptide inhibitors was designed, synthesized, and evaluated against the NS2B-NS3 proteases of the four subtypes of dengue virus, DEN-1-4. The design was based on proteochemometric models for Michaelis (Km) and cleavage rate constants (kcat) of protease substrates. This led first to octapeptides showing submicromolar or low micromolar inhibitory activities on the four proteases.

A new protolimonoid from Capuronianthus mahafalensis.

From stem barks of Capuronianthus mahafalensis (Meliaceae) endemic to Madagascar, a new protolimonoid named capulin containing a four membered ring in its side chain was isolated by repeated silica gel column chromatography. Its structure was determined by 1D and 2D NMR spectroscopy and high-resolution MS. To the best of our knowledge, this is the first time that a four-membered ring occurs in the side chain of protolimonoids.

Oligomerization of indole derivatives with incorporation of thiols.

Two molecules of indole derivative, e.g. indole-5-carboxylic acid, reacted with one molecule of thiol, e.

Design and synthesis of a library of tertiary amides: evaluation as mimetics of the melanocortins' active core.

Two hundred and ten tertiary amides were prepared on solid phase. Diamines were coupled to activated carboxylated Wang polymer, and the polymeric substituted benzyloxycarbonyl protected diamines obtained were reacted with aldehydes or ketones in trimethyl orthoformate giving resin attached Schiff bases. Coupled resins were then reduced to secondary amines by sodium cyanoborohydride in 4% acetic acid/trimethyl orthoformate, followed by acylation with the carboxylic acid in the presence of PyBroP and diisopropylethylamine.

N-alkylated dipeptide amides and related structures as imitations of the melanocortins' active core.

Thirty-three low molecular mass structures combining both peptide and peptoid features were prepared and tested on human melanocortin receptors MC1,3-5R. Most of them displayed low micromolar activity with preference for diamines, guanidino and 2-naphthyl derivatives compared to monoacetylated, amino and 3-indolyl counterparts. Some contained L- or D-histidine residues, but the change did not influence affinity.

New substituted piperazines as ligands for melanocortin receptors. Correlation to the X-ray structure of "THIQ".

A series of piperazine analogues of the melanocortin 4 receptor (MC4R) specific small-molecule agonist "THIQ" was synthesized and characterized structurally and pharmacologically. First, several THIQ imitations lacking the triazole moiety were prepared. Syntheses included acylation of 4-phenylpiperazine or 4-cyclohexylpiperazine.