Synthesis, evaluation against Leishmania amazonensis and cytotoxicity assays in macrophages of sixteen new congeners Morita–Baylis–Hillman adducts

We report the design, synthesis, in vitro evaluation against Leishmania amazonensis (IC 50), cytotoxicity assays in macrophages (CC 50), and selectivity index (SI CC 50/IC 50) of sixteen new congeners aromatic Morita–Baylis–Hillman adducts 1– 16. The 1– 16 were prepared in good to excellent yields (...

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Published in:	European journal of medicinal chemistry Vol. 46; no. 9; pp. 4295 - 4301
Main Authors:	Silva, Fábio P.L., de Assis, Priscilla A.C., Junior, Claudio G.L., de Andrade, Natália G., da Cunha, Saraghina M.D., Oliveira, Márcia R., Vasconcellos, Mário L.A.A.
Format:	Journal Article
Language:	English
Published:	Kidlington Elsevier Masson SAS 01-09-2011 Elsevier
Subjects:	Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiparasitic agents Antiprotozoal Agents - chemical synthesis Antiprotozoal Agents - chemistry Antiprotozoal Agents - pharmacology Bioisoterism Biological and medical sciences Cells, Cultured Inhibitory Concentration 50 Leishmania - drug effects Leishmania amazonensis Leishmaniasis Lipophilicity Macrophages - parasitology Magnetic Resonance Spectroscopy Mass Spectrometry Medical sciences Mice Molecular modification strategy Morita–Baylis–Hillman adducts Pharmacology. Drug treatments Spectrophotometry, Infrared Bioisoterism Leishmaniasis Morita–Baylis–Hillman adducts Leishmania amazonensis Lipophilicity Molecular modification strategy Hydroxyester Toxicity Cytotoxicity Pyridine derivatives Antiprotozoal agent Structure activity relation Vinylic compound Chemical synthesis Molecular adduct Kinetoplastida Protozoa Rodentia Benzene derivatives Naphthalene derivatives In vitro Primary alcohol Vertebrata Mammalia Mouse Animal Parasiticide Baylis-Hillman reaction Morita―Baylis―Hillman adducts Macrophage Promastigote
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Summary:	We report the design, synthesis, in vitro evaluation against Leishmania amazonensis (IC 50), cytotoxicity assays in macrophages (CC 50), and selectivity index (SI CC 50/IC 50) of sixteen new congeners aromatic Morita–Baylis–Hillman adducts 1– 16. The 1– 16 were prepared in good to excellent yields (58%–97%) from the “one pot” Morita–Baylis–Hillman Reaction between the aldehydes 29– 36 and the acrylates 27 or 28 under DABCO as promoter. The MBHA 2-[Hydroxy(2-nitrophenyl)propyl] propanoate ( 1, IC 50 = 7.52 μg/mL or 28.38 μM; CC 50 = 35.77 μg/mL or 134.98 μM; SI = 4.75) and 2-[Hydroxy(2-nitrophenyl)hydroxyethyl] propanoate ( 9, IC 50 = 5.48 μg/mL or 20.52 μM; CC 50 = 29.81 μg/mL or 111.64c μM and, SI = 5.43) were the most effective and safe evaluated compounds. The “one pot” synthesis (58%–97%) of sixteen new Morita–Baylis–Hillman adducts 1– 16 was presented. All compounds were screened against Leishmania amazonensis (IC 50), cytotoxicities assay in macrophages (CC 50), and the Selectivity Index (SI = IC 50/CC 50) were calculated for this new promising class of anti-parasitic compounds. [Display omitted] ► Aromatic Morita–Baylis–Hillman adducts (MBHA) were active compounds against the Leishmania amazonensis. ► We used the classic bioisosterism strategy for molecular modification, to idealize the new congeners MBHA. ► All new adducts were very active against L. amazonensis and the most of the selectivity indexes (SI) were greater than 1.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2011.06.036