ABSTRACT
Malaria remains one of the deadliest infectious diseases worldwide and continues to infect hundreds of millions of individuals each year. Here we report the discovery and derivatization of a series of 2,6-dibenzylidenecyclohexanones targeting the chloroquine-sensitive 3D7 strain of Plasmodium falciparum . While the initial lead compound displayed significant toxicity in a human cell proliferation assay, we were able to identify a derivative with no detectable toxicity and sub-micromolar potency.
Subject(s)
Antimalarials/pharmacology , Chloroquine/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Antimalarials/chemistry , Cell Proliferation/drug effects , Chloroquine/chemical synthesis , Chloroquine/chemistry , Dose-Response Relationship, Drug , Fibroblasts/drug effects , Humans , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
A synthetic process for the preparation of a variety of 1-aryl-1H-pyrazole-5-amines was developed. The microwave-mediated nature of this method makes it efficient in both time and resources and utilizes water as the solvent. 3-Aminocrotononitrile or an appropriate α-cyanoketone is combined with an aryl hydrazine and dissolved in 1 M HCl. The mixture is then heated in a microwave reactor at 150 °C, typically for 10-15 min. The product can be readily obtained by basifying the solution with 10% NaOH and isolating the desired compound with a simple vacuum filtration. The use of water as a solvent in this reaction lends to its ease and utility in production, and this method is easily reproducible with a variety of functional groups. Typical isolated yields range from 70-90%, and reactions can be performed on the milligram to gram scale with little to no change in observed yields. Some of the applications of these molecules and their derivatives include pesticides, anti-malarials, and chemotherapeutics, among many others.
