neocryptolepine and quinoline

Indoloquinoline (IQ) is an important class of naturally occurring antimalarial alkaloids, mainly represented by cryptolepine, isocryptolepine, and neocryptolepine. The IQ structural framework consists of four isomeric ring systems differing via the linkage of indole with quinoline as [3,2-b], [3,2-c], [2,3-c], and [2,3-b]. Structurally, IQs are planar and thus they bind strongly to the DNA which largely contributes to their biological properties. The structural rigidity and associated nonspecific cellular toxicity is a key shortcoming of the IQ structural framework for preclinical development. Thus, the lead optimization efforts were aimed at improving the therapeutic window and ADME properties of IQs. The structural modifications mainly involved attaching the basic aminoalkyl chains that positively modulates the vital physicochemical and topological parameters, thereby improves biological activity. Our analysis has found that the aminoalkylation consistently improved the selectivity index and provided acceptable in-vivo antimalarial/anticancer activity. Herein, we critically review the role of aminoalkylation in deciphering the antimalarial and cytotoxic activity of IQs.

Topics: Alkaloids; Antimalarials; Antineoplastic Agents; Cell Proliferation; Indoles; Malaria; Molecular Structure; Neoplasms; Quinolines

A facile, efficient, three-step protocol for the synthesis of the unknown quinolino[2,3-c]cinnoline 5 is introduced. In addition, a new approach for the preparation of the biologically active neocryptolepines 8 in good overall yields is described.

Topics: Alkaloids; Crystallography, X-Ray; Heterocyclic Compounds, 2-Ring; Models, Molecular; Molecular Structure; Oxidation-Reduction; Quinolines