Synthesis and antiplasmodial activity of novel chloroquine analogues with bulky basic side chains
Articolo
Data di Pubblicazione:
2015
Citazione:
Synthesis and antiplasmodial activity of novel chloroquine analogues with bulky basic side chains / B. Tasso, F. Novelli, M. Tonelli, A. Barteselli, N. Basilico, S. Parapini, D. Taramelli, A. Sparatore, F. Sparatore. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 10:9(2015 Sep 01), pp. 1570-1583. [10.1002/cmdc.201500195]
Abstract:
Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P.falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
antiprotozoal agents; chloroquine; cytisine derivatives; medicinal chemistry; quinolizidine derivatives
Elenco autori:
B. Tasso, F. Novelli, M. Tonelli, A. Barteselli, N. Basilico, S. Parapini, D. Taramelli, A. Sparatore, F. Sparatore
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