Antileishmanial and Antimalarial Chalcones: Synthesis, Efficacy and Cytotoxicity of Pyridinyl and Naphthalenyl Analogs

C.   E.   Gutteridge; J.   V.   Vo; C.   B.   Tillett; J.   A.   Vigilante; J.   R.   Dettmer; S.   L.   Patterson; K.   A.   Werbovetz; J.      Capers; D.   A.   Nichols; A.   K.   Bhattacharjee; L.      Gerena

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 μM), along with three other potent compounds (IC50 < 5 μM), 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 μM). 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.

Keywords: Leishmaniasis, malaria, chalcone, propenone, structure activity relationship, cytotoxicity