Alkaloids with Anti-Onchocercal Activity from Voacanga africana Stapf (Apocynaceae): Identification and Molecular Modeling

A new iboga-vobasine-type isomeric bisindole alkaloid named voacamine A (1), along with eight known compounds—voacangine (2), voacristine (3), coronaridine (4), tabernanthine (5), iboxygaine (6), voacamine (7), voacorine (8) and conoduramine (9)—were isolated from the stem bark of Voacangaafricana. The structures of the compounds were determined by comprehensive spectroscopic analyses. Compounds 1, 2, 3, 4, 6, 7 and 8 were found to inhibit the motility of both the microfilariae (Mf) and adult male worms of Onchocerca ochengi, in a dose-dependent manner, but were only moderately active on the adult female worms upon biochemical assessment at 30 μM drug concentrations. The IC₅₀ values of the isolates are 2.49–5.49 µM for microfilariae and 3.45–17.87 µM for adult males. Homology modeling was used to generate a 3D model of the O. ochengi thioredoxin reductase target and docking simulation, followed by molecular dynamics and binding free energy calculations attempted to offer an explanation of the anti-onchocercal structure–activity relationship (SAR) of the isolated compounds. These alkaloids are new potential leads for the development of antifilarial drugs. The results of this study validate the traditional use of V. africana in the treatment of human onchocerciasis.     

Condensation reactions of indole with acetophenones affording mixtures of 3,3-(1-phenylethane-1,1-diyl)bis(1H-indoles) and 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-diphenylcyclopent[b]indoles

Condensation of indole 1a with eight acetophenones 8a–h in ethanolic HCl afforded the corresponding mixtures of condensation products: 3,3-(1-phenylethane-1,1-diyl)bis(1H-indoles) 11a–h (2:1 condensation of indole:acetophenone, –H₂O) and diastereomers of substituted 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-diphenylcyclopent[b]indoles 12a–h and 13a–h (2:2 condensation of indole:acetophenone, –2H₂O). Each mixture was analyzed by ¹H NMR. The use of substituted electron-withdrawing acetophenones favored formation of 2:1 condensation products, whereas the use of substituted electron-donating acetophenones favored formation of 2:2 condensation products. Increased reaction temperature gave higher 2:2 condensation yields, but temperatures above 40?°C were unfavorable, giving complex, tarry mixtures.     

Highly modulated bisindoles: ligands for copper‐catalyzed Sonogashira reaction

Bisindoles (BIMs) were modulated as powerful N,N′ donor ligands for the copper‐catalyzed Sonogashira reaction. Ligand screening experiments on 11 BIM compounds found that 3,3′‐(4‐chlorophenyl)methylenebis(1‐methyl‐1H‐indole) (10%) efficiently accelerated CuCl (5%)‐catalyzed cross‐coupling of aryl iodides with terminal alkynes. A wide range of substituted aryl iodides and/or alkyl‐ and aryl‐substituted terminal alkynes were examined, leading to the corresponding coupling products with yields up to 99%. An efficient and scalable protocol for the synthesis of BIM ligands on a gram scale, with extremely low catalyst loading of o‐ClC₆H₄NH₃⁺Cl^?, was also developed with a reaction time of 20 min with yields up to 93%. This novel N,N′ ligand was air‐stable, easily available and highly modulated with low copper loading. Copyright © 2016 John Wiley & Sons, Ltd.     

Pd/C‐Catalyzed Cyclizative Cross‐Coupling of Two ortho‐Alkynylanilines under Aerobic Conditions: Synthesis of 2,3′‐Bisindoles

A palladium‐catalyzed cyclizative cross‐coupling of two o‐alkynylanilines to 2,3′‐bisindoles under aerobic oxidative conditions was developed. Mechanistic studies suggested that the two catalytic cycles, namely the formation of 3‐alkynylindoles 8 and their subsequent cyclization to bisindoles 5 , are temporally separated. The aminopalladation of 3‐alkynylindoles 8 occurred only after all the N,N‐dialkyl‐o‐alkynylanilines were consumed. The solid support (activated charcoal) played a crucial role in the second intramolecular aminopalladation process.