Design, synthesis, and antiplasmodial evaluation of a series of novel sulfoximine analogues of carbohydrate‐based thiochromans

Abstract

Sulfone/sulfoxide-containing carbohydrate derived thiochromans were found to be highly active antiplasmodial agents. However, the inability of the sulfone/sulfoxide functional groups for further derivatization and manipulation limited the potential for further exploration. In this study, based on the interesting and important physicochemical properties, as well as amenability of sulfoximines (isosters of sulfones) for further derivatization, a series of novel sulfoximine-type carbohydrate-derived thiochroman derivatives have been successfully synthesized, characterized, and evaluated for their antiplasmodial activity. Although the replacement of the sulfone functional group with a sulfoximine unit improved the antiplasmodial activity of the scaffolds, the activity was highly dependent on the configuration of the stereogenic centre at the sulfur atom. Moreover, analysis of the crystal structures of the sulfoximine analogues revealed that the bond between the sulfur and nitrogen atoms of the sulfoximine functional group is not a true double bond but rather a polarized single bond. K E Y W O R D Santimalarial, antiplasmodial, sulfoximine, thiochroman

Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry

“…Additionally, all investigated compounds were not cytotoxic against HeLa cells at 20 μM. 149 The phenyl residue or the triazole moiety was not examined; hence, the authors concluded that 71 may serve as a prototype for novel derivatives with improved antiplasmodial activities. Further investigations of the SAR, ADME profile, and in vivo potency of this class of compounds are needed to reach clinical trials.…”

“…(A) Chemical structures and IC 50 values of the parent carbohydrate-based thiochroman 69 and its sulfoximine analogues 70a / b . (B) chemical structure and IC 50 value of the most potent sulfoximine-triazole hybrid 71 . ,,, …”

“…The antimalarial activity was shown to be highly dependent on a long alkyl chain, since analogues with shorter alkyl chains (e.g., methyl or butyl) and precursors of 71 were inactive. Additionally, all investigated compounds were not cytotoxic against HeLa cells at 20 μM . The phenyl residue or the triazole moiety was not examined; hence, the authors concluded that 71 may serve as a prototype for novel derivatives with improved antiplasmodial activities.…”

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…As part of their broader studies in carbohydrate chemistry, Kinfe et al. described the synthesis and biological activity of a series of carbohydrate derived thiochromans, which possessed sub‐micromolar activity against chloroquine‐sensitive and ‐resistant strains in vitro In order to further explore this class of compounds, Chizema et al., explored bioisosteric replacement of the sulfone functionality with a sulfoximine (e. g., 71 ), which in addition to favourable physicochemical properties, and metabolic stability, has the distinct advantage of introduction of a stereogenic centre, which can be further functionalised . Following biological assessment, these compounds were generally found to be moderate anti‐plasmodials, with activities in the low‐micromolar range, and represent an interesting scaffold for further elaboration …”

One-Pot Synthesis of N-Iodo Sulfoximines from Sulfides

“…The increasing interest in sulfoximines − in drug discovery, − medicine, − and agrochemistry , has led to a rapidly growing number of publications − in these and other research areas . These compounds are of great importance as ligands, auxiliaries, and catalysts, e.g., in asymmetric synthesis and catalysis. , Recently, a large number of reports on their synthesis and transformations have appeared in the literature, − including halo- and chalcogenations.…”