Structure of the Antiplasmodial Compound 7,9-Dinitrocryptolepine Hydrochloride Methanol Solvate

Abstract

The structure of C₁₆H₁₀N₄O₄[HCl,1.5CH₃OH], M_r = 406.80, has been determined from X-ray diffraction data. The crystals are monoclinic, space group C2/c, with eight molecules per unit cell and a = 21.482(4), b = 7.131(1), c = 24.495(5) Å, β = 111.01(3)°, crystal density D_c = 1.546 g/cm³. The material was difficult to crystallize and crystals produced were found to be poor diffractors. Intensity data were measured at liquid nitrogen temperature using a weakly diffracting crystal typical of the batch. However the X-ray analysis has finally enabled the chemical constitution of this cryptolepine derivative, which was previously incorrectly assigned, to be unequivocally established. Direct methods were used to solve the structure which was refined by full-matrix least squares to a conventional R-index of 0.0798 for 2,861 reflections and 268 parameters. The 7,9-dinitrocryptolepine molecule is highly planar with a strong intramolecular hydrogen bond between N(10) in ring C and O(92) of a nitro group. There are a number of intermolecular hydrogen bonds involving the cryptolepine derivative the hydrochloride and both solvated methanols. One of the methanol solvate molecules (methanol 2) is unusually disordered with its C atom lying exactly on a crystallographic twofold axis. Consequently the methanol OH and H₃ groups are at 0.5 occupancy and repeated by the twofold symmetry.

Graphical Abstract

Cryptolepine (5-methyl, 10H-indolo[3,2-b]quinoline) the principal constituent of Cryptolepis sanguinolenta (Periplocaceae) is currently of interest as a lead compound for the development of both antimalarial and anticancer agents. Cryptolepine has potent activity against malaria parasites in vitro, but it is also cytotoxic on account of its abilities to intercalate into DNA, inhibit DNA synthesis and inhibit topoisomerase II. The 7,9-dinitroanalogue of cryptolepine was synthesised as part of a program designed to discover new antimalarial and anticancer agents. The X-ray structure of this compound will help to determine whether or not 7,9-dinitrocryptolepine is able to intercalate into DNA and facilitate the design of new cryptolepine analogues with DNA binding properties appropriate for antimalarial (with no DNA intercalation) or anticancer (sequence-specific binding) applications.