The role of plasmodium falciparum food vacuole plasmepsins

Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin-degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo-aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high-antiparasitic activities in P. falciparum-infected erythrocytes it is necessary to inhibit several of the haemoglobin-degrading plasmepsins. Herein we summarize the structure-activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared.

Plasmepsins as potential targets for new antimalarial therapy

The synthesis and evaluation of structural analogues and isosteres are of central importance in medicinal and agricultural chemistry. The sulfonamide functional group represents one of the most important amide isosteres in contemporary drug design, and about 500 such compounds have overcome both the pharmacological and regulatory hurdles that precede studies in humans. The mono aza analogues of sulfonamides, that is, sulfonimidamides, are rapidly gaining popularity as a novel functional group among synthetic chemists involved in the design of biologically active compounds for both pharmaceutical and agrochemical applications. Herein, we review these recent developments to showcase the promise of this functional group.

Sulfonimidamides in Medicinal and Agricultural Chemistry.

https://www.hal.inserm.fr/inserm-00491874/document

Pathophysiological functions of cathepsin D: Targeting its catalytic activity versus its protein binding activity?

The selective and efficient C-H methylation of sp2 and sp3 carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound changes to physicochemical properties attributed to the installation of a "Magic Methyl" group at a strategic site in a lead compound, such techniques have become highly desirable in modern drug discovery and synthesis programmes. This review will cover the diverse techniques that have been employed to enable the selective installation of the C-Me bond in a wide range of chemical structures, from simple building blocks to complex drug-like architectures.

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Installing the "magic methyl"- C-H methylation in synthesis.

Methylation is a well-known structural modification in organic and medicinal chemistry. This review summarizes recent advances in methylation by categorizing specific methylation reagents. The challenges of mono N-methylation of aliphatic amines and N-methylation of peptides are discussed. This review will be useful for chemists wanting to select the appropriate reagents for methylation chemistry. Based on the large diversity of methylation reagents and their wide scope, this review also broadens perspectives on which strategies to select for utilizing a particular methylation, resulting in an increased flexibility in synthetic route planning.

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 microM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.

Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II. Use of solid-phase synthesis to explore novel statine motifs.

Sulfonimidamides were prepared in a one-pot transformation from sulfonamides, through nucleophilic substitution of sulfonimidoyl chlorides formed in situ with different amines. This methodology represents a convenient, safe, and easily accessible synthetic route to sulfonimidamides.

A convenient synthetic route to sulfonimidamides from sulfonamides

Sulfonamides are common building blocks in organic synthesis. They have a wide range of medical applications. This review aims to delineate recent efforts towards the functionalization of primary sulfonamides during last three years and to provide an overview of the synthesis of N-alkylated, N-acylated, and N-arylated sulfonamides from primary sulfonamides. Among other reactions, the sulfonamide-directed C–H functionalization is highlighted. 1 	Application of Sulfonamides 2 	Synthesis of N-Alkylated Sulfonamides 3 	Synthesis of N-Acylated Sulfonamides 4 	Synthesis of N-Arylated Sulfonamides 5 	Other Chemistry 6 	Summary and Perspective

Recent Functionalizations of Primary Sulfonamides

Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster B), and two new types of aza-saccharins (clusters C and D). We demonstrate a convenient protocol to selectively synthesize products in cluster C or D when primary amines are used. Preclinical characterization of selected matched-pair products is reported. Through comparison of two diastereomers, we highlight how stereochemistry affects the preclinical properties. Given that saccharin-based derivatives are widely used in many chemistry fields, we foresee that structures exemplified by clusters C and D offer new opportunities for novel drug design, creating a chiral center on the sulfur atom and the option of substitution at two different nitrogens.

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Yantao Chen

Papers

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II. Use of solid-phase synthesis to explore novel statine motifs.

A convenient synthetic route to sulfonimidamides from sulfonamides

Recent Functionalizations of Primary Sulfonamides

Saccharin Aza Bioisosteres—Synthesis and Preclinical Property Comparisons