Subtopic Deep Dive
Sulfoximine Applications in Medicinal Chemistry
Research Guide
What is Sulfoximine Applications in Medicinal Chemistry?
Sulfoximine applications in medicinal chemistry involve the synthesis and incorporation of sulfoximine motifs as bioisosteres in drug candidates to enhance metabolic stability and binding affinity, particularly in kinase inhibitors.
Sulfoximines serve as sulfur(VI) pharmacophores replacing sulfones in medicinal chemistry for improved pharmacokinetics. Key studies demonstrate their use in clinical candidates like roniciclib and BAY 1143572 analogs (Sirvent and Lücking, 2017, 202 citations). Over 300 papers explore synthesis methods and drug-like properties since 2015.
Why It Matters
Sulfoximines address metabolic liabilities of sulfone-based drugs by offering unique pharmacophores with enhanced selectivity in kinase inhibition (Lücking, 2019, 327 citations). Bayer's drug discovery programs utilized sulfoximines in pan-CDK and P-TEFb inhibitors, improving clinical outcomes (Sirvent and Lücking, 2017). Bioisosteric replacement strategies extend to agricultural compounds, modulating potency and physicochemical properties (Meanwell, 2023, 162 citations).
Key Research Challenges
Scalable NH-Sulfoximine Synthesis
Direct NH transfer to sulfoxides requires mild conditions to avoid over-oxidation, with protocols using ammonia sources achieving high yields (Zenzola et al., 2016, 217 citations). Scalability remains limited for pharmaceutical production. Alternative electrophilic NH reagents improve accessibility (Gasser et al., 2022, 84 citations).
Chiral Sulfoximine Construction
Asymmetric synthesis of chiral sulfoximines demands precise stereocontrol for bioactive enantiomers in drug design. Condensation methods yield chiral sulfinates but require optimization for sulfoximine extension (Zhang et al., 2022, 128 citations). Organocatalytic approaches lag behind sulfone analogs.
Sulfonimidamide Analog Evaluation
One-pot synthesis of unprotected sulfonimidamides from sulfinamides enables drug-like scaffolds, but biological profiling is underdeveloped (Izzo et al., 2017, 99 citations). Metabolic stability comparisons to sulfoximines need more kinase inhibitor case studies.
Essential Papers
A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry
Carlo Sambiagio, David Schönbauer, Rémi Blieck et al. · 2018 · Chemical Society Reviews · 1.6K citations
The present review is devoted to summarizing the recent advances (2015–2017) in the field of metal-catalysed group-directed C–H functionalisation.
Neglected sulfur(<scp>vi</scp>) pharmacophores in drug discovery: exploration of novel chemical space by the interplay of drug design and method development
Ulrich Lücking · 2019 · Organic Chemistry Frontiers · 327 citations
The key learnings of the utilization of sulfoximines, sulfondiimines and sulfonimidamides in drug discovery at Bayer AG are shared.
Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides
Marina Zenzola, Robert Doran, Leonardo Degennaro et al. · 2016 · Angewandte Chemie International Edition · 217 citations
Abstract A new system for NH transfer is developed for the preparation of sulfoximines, which are emerging as valuable motifs for drug discovery. The protocol employs readily available sources of n...
Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates
Juan Alberto Sirvent, Ulrich Lücking · 2017 · ChemMedChem · 202 citations
Abstract Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, ron...
Applications of Bioisosteres in the Design of Biologically Active Compounds
Nicholas A. Meanwell · 2023 · Journal of Agricultural and Food Chemistry · 162 citations
The design of bioisosteres represents a creative and productive approach to improve a molecule, including by enhancing potency, addressing pharmacokinetic challenges, reducing off-target liabilitie...
Synthesis of chiral sulfinate esters by asymmetric condensation
Xin Zhang, Esther Cai Xia Ang, Ziqi Yang et al. · 2022 · Nature · 128 citations
A New, Practical One‐Pot Synthesis of Unprotected Sulfonimidamides by Transfer of Electrophilic NH to Sulfinamides
Flavia Izzo, Martina Schäfer, Robert A. Stockman et al. · 2017 · Chemistry - A European Journal · 99 citations
Abstract Unprotected tertiary sulfonimidamides have been prepared in good to excellent yields in a one‐pot transformation from tertiary sulfinamides through NH transfer. The reaction is mediated by...
Reading Guide
Foundational Papers
Start with Bolm et al. (2014) for pentafluorosulfanylphenyl sulfoximine synthesis and Chen and Bolm (2014) for bioactive derivatives, as they establish early medicinal scaffolds with low-cost routes.
Recent Advances
Study Lücking (2019) for sulfur(VI) pharmacophore overview and Sirvent and Lücking (2017) for kinase inhibitor analogs, capturing Bayer's clinical advances.
Core Methods
Core techniques include NH-transfer to sulfoxides (Zenzola et al., 2016), one-pot sulfonimidamide synthesis (Izzo et al., 2017), and asymmetric sulfinate condensation (Zhang et al., 2022).
How PapersFlow Helps You Research Sulfoximine Applications in Medicinal Chemistry
Discover & Search
Research Agent uses searchPapers and exaSearch to retrieve sulfoximine drug papers like 'Neglected sulfur(VI) pharmacophores' by Lücking (2019), then citationGraph reveals 327 citing works on Bayer analogs, while findSimilarPapers uncovers bioisostere reviews.
Analyze & Verify
Analysis Agent employs readPaperContent on Zenzola et al. (2016) to extract NH-transfer yields, verifies claims with CoVe against 10 similar syntheses, and runPythonAnalysis computes statistical stability metrics from sulfoximine ADME data using pandas, graded by GRADE for evidence strength.
Synthesize & Write
Synthesis Agent detects gaps in chiral sulfoximine kinase inhibitors via contradiction flagging across Lücking papers, then Writing Agent uses latexEditText, latexSyncCitations for Sirvent (2017), and latexCompile to generate a review manuscript with exportMermaid for bioisostere comparison diagrams.
Use Cases
"Analyze metabolic stability data from sulfoximine kinase inhibitors in Bayer papers."
Research Agent → searchPapers → Analysis Agent → readPaperContent (Lücking 2019) → runPythonAnalysis (pandas plot ADME trends) → statistical verification output with GRADE scores.
"Draft LaTeX section on NH-sulfoximine synthesis for drug design review."
Synthesis Agent → gap detection → Writing Agent → latexEditText (insert Zenzola 2016 methods) → latexSyncCitations → latexCompile → formatted PDF section with diagrams.
"Find open-source code for sulfoximine synthesis simulations."
Research Agent → paperExtractUrls (Zhang 2022) → paperFindGithubRepo → githubRepoInspect → Code Discovery workflow outputs Python scripts for chiral modeling.
Automated Workflows
Deep Research workflow scans 50+ sulfoximine papers via citationGraph from Lücking (2019), generating structured reports on kinase applications with CoVe checkpoints. DeepScan applies 7-step analysis to Bolm (2014) synthesis, verifying scalability with runPythonAnalysis. Theorizer hypothesizes novel bioisosteres by synthesizing motifs from Sirvent (2017) and Meanwell (2023).
Frequently Asked Questions
What defines sulfoximine applications in medicinal chemistry?
Sulfoximines act as bioisosteres for sulfones in drug design, enhancing pharmacokinetics in kinase inhibitors like roniciclib analogs (Sirvent and Lücking, 2017).
What are key synthesis methods for NH-sulfoximines?
Direct NH transfer from ammonia sources to sulfoxides uses electrophilic systems (Zenzola et al., 2016, 217 citations); one-pot sulfinamide routes employ diacetoxyiodobenzene (Izzo et al., 2017).
Which papers establish sulfoximines in drug discovery?
Lücking (2019, 327 citations) reviews Bayer's sulfur(VI) pharmacophores; Sirvent and Lücking (2017, 202 citations) evaluate clinical candidate analogs.
What open problems exist in sulfoximine medicinal chemistry?
Challenges include scalable chiral synthesis and expanded biological profiling beyond kinases; gaps persist in sulfonimidamide stability data (Izzo et al., 2017).
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Part of the Synthesis and Catalytic Reactions Research Guide