Synthesis and in vitro antimalarial activity of a series of bisquinoline and bispyrrolo[1,2a]quinoxaline compounds

• Published in: European journal of medicinal chemistry 2012-09, Vol.55, p.335-345
• Main Authors: van Heerden, Lezanne, Cloete, Theunis T., Breytenbach, J. Wilma, de Kock, Carmen, Smith, Peter J., Breytenbach, Jaco C., N’Da, David D.
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antimalarials - toxicity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Biological and medical sciences; Bispyrroloquinoxalines; Bisquinolines; Cell Line, Tumor; Chemistry Techniques, Synthetic; CHO Cells; Cricetinae; Cricetulus; Cytotoxicity; Humans; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Plasmodium falciparum; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Quinolines - toxicity; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Quinoxalines - toxicity; Solubility; Water - chemistry
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.07.037

Series of bisquinolines 4–15 and bispyrrolo[1,2a]quinoxalines 16–20 containing various polyamine linkers were synthesized. The aqueous solubility and distribution coefficient were experimentally determined. The compounds were screened for antimalarial activity alongside chloroquine against D10 and Dd2 strains of Plasmodium falciparum. The growth inhibitory effects of biscompounds 4–9 were assessed against various cancer cell lines. The aqueous solubility was found to increase with an increase in potential proton.ation sites. Bisquinolines 8 and 9 featuring triethylenetetramine and N,N′-bis(3-aminopropyl)ethylene-diamine linkers, respectively, were the most active of all synthesized compounds. They were found as potent as chloroquine against D10 but significantly more potent against the Dd2 strain, with good selectivity towards parasitic cells. Compound 4 containing a diethylenetriamine bridge displayed the most important anticancer activity of the series, and was a more effective antiproliferative inhibitor than etoposide against all three TK10, UACC62 and MCF7 cancer cell lines. Series of bisquinoline and bispyrrolo[1,2a]quinoxaline compounds were synthesized and their in vitro antimalarial activity as well as cytotoxicity were determined. [Display omitted] ► Synthesis of a series of bisquinolines and bispyrroloquinoxalines. ► Evaluation of antimalarial activity of series. ► Bisquinolines are more active than bispyrroloquinoxalines. ► Bis(7-chloroquinoline)s are more potent than chloroquine against Dd2 strain.