Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.

Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome β5 active-site (Pfβ5).

Enzymatic Resolution and Decarboxylative Functionalization of α-Sulfinyl Esters.

α-Sulfinyl esters can be readily prepared through thiol substitution of α-bromo esters followed by oxidation to the sulfoxide. Enzymatic resolution with lipoprotein lipase provides both the unreacted esters and corresponding α-sulfinyl carboxylic acids in high yields and enantiomeric ratios. Subsequent decarboxylative halogenation, dihalogenation, trihalogenation and cross-coupling gives rise to functionalized sulfoxides.

Fast-Killing Tyrosine Amide (()-SW228703) with Blood- and Liver-Stage Antimalarial Activity Associated with the Cyclic Amine Resistance Locus (CARL).

Current malaria treatments are threatened by drug resistance, and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified ()-SW228703 (()-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to ()-SW703 is associated with mutations in the cyclic amine resistance locus (CARL) and acetyl CoA transporter (ACT), similarly to several other compounds that share features such as fast activity and liver-stage activity.

Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in .

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity.

An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Tubulin Polymerization.

The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC values from 50 to 480 nM.

Total synthesis of haliclamide.

A stereoselective approach for the synthesis of haliclamide 1, a marine natural product, has been developed. The notable features of our synthesis include MacMillan cross aldol, Mitsunobu inversion, Yamaguchi-Hirao alkylation, Steglich esterification and macrolactamization reactions and the Corey-Fuchs protocol as the key steps.