title: Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.
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.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16131 Genova (Italy). bruno.tasso@unige.it.
authors.forename: Bruno
authors.initials: B
authors.lastname: Tasso
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16131 Genova (Italy).
authors.forename: Federica
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16131 Genova (Italy).
authors.forename: Michele
authors.initials: M
authors.lastname: Tonelli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano via Mangiagalli 25, 20133 Milano (Italy).
authors.forename: Anna
authors.initials: A
authors.lastname: Barteselli
authors.affiliation: Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano via C. Pascal 36, 20133 Milano (Italy).
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano via C. Pascal, 36, 20133 Milano (Italy).
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano via C. Pascal, 36, 20133 Milano (Italy).
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano via Mangiagalli 25, 20133 Milano (Italy).
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16131 Genova (Italy).
authors.forename: Fabio
authors.initials: F
authors.lastname: Sparatore
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000737:chemistry; D004351:Drug Resistance / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D002738:Chloroquine
keywords: antiprotozoal agents; chloroquine; cytisine derivatives; medicinal chemistry; quinolizidine derivatives