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
Medicinal Chemistry
Title: Antileishmanial and Antimalarial Chalcones: Synthesis, Efficacy and Cytotoxicity of Pyridinyl and Naphthalenyl Analogs
Volume: 3 Issue: 2
Author(s): 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 and L. Gerena
Affiliation:
Keywords: Leishmaniasis, malaria, chalcone, propenone, structure activity relationship, cytotoxicity
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.
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Gutteridge E. C., Vo V. J., Tillett B. C., Vigilante A. J., Dettmer R. J., Patterson L. S., Werbovetz A. K., Capers J., Nichols A. D., Bhattacharjee K. A. and Gerena L., Antileishmanial and Antimalarial Chalcones: Synthesis, Efficacy and Cytotoxicity of Pyridinyl and Naphthalenyl Analogs, Medicinal Chemistry 2007; 3 (2) . https://dx.doi.org/10.2174/157340607780059530
DOI https://dx.doi.org/10.2174/157340607780059530 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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