The importance of sulfur-containing motifs in drug design and discovery

ABSTRACT

Introduction

Sulfur-containing functional groups are privileged motifs that occur in various pharmacologically effective substances and several natural products. Various functionalities are found with a sulfur atom at diverse oxidation states, as illustrated by thioether, sulfoxide, sulfone, sulfonamide, sulfamate, and sulfamide functions. They are valuable scaffolds in the field of medicinal chemistry and are part of a large array of approved drugs and clinical candidates.

Area Covered

Herein, the authors review the current research on the development of organosulfur-based drug discovery. This article also covers details of their roles in the new lead compounds reported in the literature over the past five years 2017–2021.

Expert opinion

Given its prominent role in medicinal chemistry and its importance in drug discovery, sulfur has attracted continuing interest and has been used in the design of various valuable compounds that demonstrate a variety of biological and pharmacological feature activities. Overall, sulfur’s role in medicinal chemistry continues to grow. However, many sulfur functionalities remain underused in small-molecule drug discovery and deserve special attention in the armamentarium for treating diverse diseases. Research efforts are also still required for the development of a synthetic methodology for direct access to these functions and late-stage functionalization.

KEYWORDS:

• Drug design
• functional groups
• organosulfur compounds
• sulfur containing drugs
• sulfur heterocycles

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• Sulfur-derived functional groups can be found in a broad range of therapeutic compounds and natural products in a wide variety of oxidation states (from –2 to +6).

• Thioether, sulfoxide, sulfone, sulfonamide, sulfamate, sulfamide, and sulfur-related heterocycles constitute the main functional armamentum used in drug design and discovery.

• About a quarter of all small-molecule pharmaceuticals currently used are organosulfur compounds.

• Organosulfur compounds play an important role in therapy and constitute a significant portion of the compounds approved by the FDA each year or entering clinical studies

• Some underused sulfur-containing functions such as sulfoximine, sulfonimidamides, sulfondiimides sulfonyl fluoride, and fluorosulfate constitute new opportunities for drug discovery and could ultimately lead to more effective and safer therapies.

Additional information

Funding

This manuscript was not funded.