title: Antileishmanial and antimalarial chalcones: synthesis, efficacy and cytotoxicity of pyridinyl and naphthalenyl analogs.
abstract: The antileishmanial and antimalarial activity of methoxy-substituted chalcones (1,3-diphenyl-2-propen-1-ones) is well established. The few analogs prepared to date where the 3-phenyl group is replaced by either a pyridine or naphthalene suggest these modifications are potency enhancing. To explore this hypothesis, sixteen 3-naphthalenyl-1-phenyl-2-prop-1-enones and ten 1-phenyl-3-pyridinyl-2-prop-1-enones were synthesized and their in vitro efficacies against Leishmania donovani and Plasmodium falciparum determined. One inhibitor with submicromolar efficacy against L. donovani was identified (IC50 = 0.95 microM), along with three other potent compounds (IC50 < 5 microM), all of which were 3-pyridin-2-yl derivatives. No inhibitors with submicromolar efficacy against P. falciparum were identified, though several potent compounds were found (IC50 < 5 microM). The cytotoxicity of the five most active L. donovani inhibitors was assessed. At best the IC50 against a primary kidney cell line was around two-fold higher than against L. donovani. Being more active than pentamidine, the 1-phenyl-3-pyridin-2-yl-2-propen-1-ones have potential for further development against leishmaniasis; however it will be essential in such a program to address not only efficacy but also their potential for toxicity.
authors.affiliation: Department of Chemistry, United States Naval Academy, Annapolis, MD 21402, USA. gutterid@usna.edu
authors.forename: C E
authors.initials: CE
authors.lastname: Gutteridge
authors.forename: J V
authors.initials: JV
authors.lastname: Vo
authors.forename: C B
authors.initials: CB
authors.lastname: Tillett
authors.forename: J A
authors.initials: JA
authors.lastname: Vigilante
authors.forename: J R
authors.initials: JR
authors.lastname: Dettmer
authors.forename: S L
authors.initials: SL
authors.lastname: Patterson
authors.forename: K A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: J
authors.initials: J
authors.lastname: Capers
authors.forename: D A
authors.initials: DA
authors.lastname: Nichols
authors.forename: A K
authors.initials: AK
authors.lastname: Bhattacharjee
authors.forename: L
authors.initials: L
authors.lastname: Gerena
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D047188:Chalcones / Q000138:chemical synthesis* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D007202:Indicators and Reagents; D007891:Leishmania / Q000187:drug effects*; D007893:Leishmania donovani / Q000187:drug effects; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D047188:Chalcones; D007202:Indicators and Reagents; D009281:Naphthalenes; D011725:Pyridines