Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains. Issue 9 (24th July 2015)

• Record Type: Journal Article
• Authors: Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio
• Is Part Of: ChemMedChem. Volume 10:Issue 9(2015:Sep.)
• Page Start: 1570
• Page End: 1583
• Publication Date: 2015-07-24
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500195
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Chloroquine is commonly used in the treatment and prevention of malaria, but <italic>Plasmodium falciparum</italic>, 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‐2<italic>H</italic>‐quinolizine and 1, 2, 3, 4, 5, 6‐hexahydro‐1, 5‐methano‐8<italic>H</italic>‐pyrido[1, 2‐<italic>a</italic>][1, 5]diazocin‐8‐one, were synthesized and tested for activity against D‐10 (CQ‐susceptible) and W‐2 (CQ‐resistant) strains of <italic>P. falciparum</italic>. 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.</p> </abstract>