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Sulfilimines: An Underexplored Bioisostere for Drug Design?

21 April 2025

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In the ever-evolving landscape of medicinal chemistry, searching for novel functional groups with optimized pharmacological properties remains a key driver of innovation. While sulfoximines have gained increasing traction as aza-analogs of sulfones in both FDA-approved drugs and agrochemicals, a newer class—sulfilimines—is now emerging as a promising, underutilized scaffold for drug design. Pioneering studies by Ellman, Gnamm, and most recently by Arvidsson and Ritter’s groups have demonstrated the chemical versatility, metabolic stability, and synthetic utility of sulfilimines in the development of bioactive molecules. As part of our commitment to advancing modern drug discovery, AmBeed offers a curated catalog of sulfur-based building blocks, including sulfilimines and related heterocyclic fragments, designed to accelerate medicinal chemistry research from hit discovery to lead optimization.

Structural and Physicochemical Highlights

Sulfilimines are characterized by a stereogenic sulfur center and a tunable nitrogen atom, providing medicinal chemists with an additional vector for molecular design. This N-substitution site can function as a hydrogen-bond donor or acceptor, offering improved control over binding interactions and pharmacokinetics (Figure 1).

These properties distinguish sulfilimines from sulfones and sulfoximines, broadening their potential as bioisosteric replacements in drug scaffolds [1].

Stability and Metabolic Properties

Recent studies have highlighted the exceptional chemical and metabolic stability of sulfilimine-containing molecules, particularly those bearing S-cyclopropyl or cyclobutyl groups. Compounds demonstrated low microsomal clearance rates in both murine and human liver systems while retaining high polarity and low molecular weight—desirable traits for oral bioavailability and tissue-specific distribution (Figure 2) [1].

Drug-Like Profiles and Therapeutic Relevance

There is a growing need for novel scaffolds that defy traditional permeability rules, especially in the context of targeted delivery systems. While sulfilimines typically exhibit limited membrane permeability, this can be advantageous in:
• Gastrointestinal or inhalation-targeted therapies
• Topical applications
• Controlled-release or liver-activated prodrug strategies
This pharmacological profile parallels imatinib analogs and supports the inclusion of sulfilimines in drug development pipelines seeking selective exposure with minimal systemic side effects [1].

Synthetic Innovation with Sulfilimines

A groundbreaking study by Cheng et al. [2] from Ritter’s group demonstrated that sulfilimines can serve as bifunctional N-centered radical precursors, enabling photoredox-driven cyclization with alkenes to form a diverse array of unprotected N-heterocycles in a single step. This method streamlines access to five-, six-, and seven-membered nitrogen-containing rings, expanding the toolbox for medicinal chemists working in heterocycle-rich chemical space (Figures 3–4).

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References

[1]Arvidsson P. I. Sulfilimines: An Underexplored Bioisostere for Drug Design? J. Med. Chem. 2025, 68(4), 4056–4058.

[2]Cheng Q., Bai Z., Tewari S., et al. Bifunctional sulfilimines enable synthesis of multiple N-heterocycles from alkenes. Nature Chemistry 2022, 14(8), 898–904.

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