Sulfoximine as rising stars in modern drug discovery

Sulfoximine first semester Credit presentation
Prashant Chavan (GPAT,NIPER Qualified)
M.S. (Pharm) in Medicinal Chemistry
National Institute of Pharmaceutical Education and Research Mohali, Punjab-160062 (India)
Mail ID- [email protected]

1. Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry 1 Presented By:- Prashant Mahadu Chavan Reg. No- 20MCM3144 M.S. 1 st Year (1 st Semester) Department of Medicinal Chemistry NIPER, S.A.S. Nagar, Mohali, Punjab

2. Flow of Presentation INTRODUCTION SULFOXIMINE: AS RISING STARS IN MODERN DRUG DISCOVERY APPROACHES FOR SYNTHESIS OF SULFOXIMINE SYNTHETIC SCHEMES OF SULFOXIMINE SULFOXIMINE AS A NOVEL LEAD STRUCTURE IN MEDICINAL CHEMISTRY CONCLUSION 2

3. INTRODUCTION Sulphur (Asymmetric): configuration stable C-H acidic position, depending on R 3 Nitrogen: nucleophilic, basic pK a (NH 2 + ) = 2.7 (in water) R 2 = additional attachment point If R 3 = H (acidic): pKa = 24 (in DMSO) 3 Lücking, U. Angew . Chem . Int . Ed . 2013 , 52 , 9399-9408

4. Sulfoximine as a rising stars in modern drug discovery 4 Figure 1. The number of publications per decade containing “sulfoximine” as keyword and reactions per decade containing sulfoximine substructure Mäder, P . et al. ACS J. Med. Chem. 2020 , 63, 23 , 14243-14275

5. Studies of Drug-Like Properties of Sulfoximine Tool Compounds and Matched Molecular Pair Analysis 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Frings, M . et al. Eur. J. Med. Chem. 2017 , 126 , 225-245

6. For assay details, ND = not determined; a no valid results were obtained; b measured at pH = 12; c no pKa/pKb was measured in the range of the assay (pH 2-12) ; d measured at pH = 2. Table 1. logP , Dissociation constants, microsomal stability, aqueous solubility and permeability assay of compounds 1-14. 6 Compound logP pKa/pKb Human Liver Microsome solubility Aqueous solubility [µg/mL] PAMPA P app [10 -6 cm/s] HPLC Assay Potentiometric Assay T 1/2 [min] %Q H HPLC Assay Shake flask assay HPLC Assay Potentiometric Assay 1 -0.3 ND ND _a _a >46 11100 _a 2 1.5 ND ND _a _a >47 300 _a 3 _a 2.0 b pKb = 2.5 >130 <23 >50 9100 6.9 4 0.1 ND no pKa/pKb c >130 <23 >54 2400 11 5 0.2 ND pKb = 3.8 >130 <23 >59 4700 9.2 6 -0.5 0.9 b pKb = 2.4 47 45 ND 6900 5.7 7 0.4 ND no pKa/pKb c >130 <23 ND 1200 9.8 8 1.5 ND no pKa/pKb c >130 <23 ND 1200 9.5 9 0.3 ND ND _a _a >44 300 _a 1 0.5 ND ND >130 <23 ND 200 5.7 11 0.2 ND ND >130 <23 ND 700 11 12 ND 1.4 d pKa = 9.4 >130 <23 >48 800 4.1 13 ND 2.4 d pKa = 10.7 >130 <23 >49 900 6.3 14 2.7 ND ND _a _a 47 90 _a Frings, M . et al. Eur. J. Med. Chem. 2017 , 126 , 225-245

7. Approaches for Synthesis of Sulfoximine 7 S-N Bond formation: S-O Bond formation: S-C Bond formation: Aota, Y. et al . Chem. – Eur. J. 2019 , 25 , 15755-15758

8. Synthesis of Methionine Sulfoximine 8 Methionine sulfoxide by Rh- catalyzed N- Boc transferred Well strategy for N-protected sulfoximine Bull, J. et al . Synlett . 2017 , 28 , 2525-2538

9. Unexpected Synthesis of Cyclic Sulfoximine 9 The first Cyclic sulfoximine was discovered in 1973 by Johnson and Janiga Slow spontaneous cyclization of cyclopropyl sulfoximine Bull, J. et al. chem. – Eue . J. 2020 , 26 , 4378-4388

10. Novel S ynthetic A pproach of Cyclic Sulfoximine 10 For one-pot synthesis Bull, Luisi and co-workers was developed new method Intramolecular alkylation at NH position Bull, J. et al. chem. – Eue . J. 2020 , 26 , 4378-4388

11. 1) Antineoplastic agent: 1.1) CDK Inhibitors: A)Pan-CDK Inhibitor: 11 IC 50 [nM] Compound CDK1/CycB CDK2/CycE CDK4/CycD1 CDK9/CycT1 VEGF-R2 CA-II 15 50 4 ND ND 34 514 16 2 3 ND ND 32 >10,000 17 7 9 11 5 163 >10,000 18 9 8 ND ND 477 >10,000 SULFOXIMINE AS NOVEL LEAD STRUCTURE IN MEDICINAL CHEMISTRY 15 16 17 18 Lücking, U. et al . Chem. Med. Chem 2013, 8 , 1067-1085 Mäder, P . et al. ACS J. Med. Chem. 2020 , 63, 23 , 14243-14275 Siemeister , G. et al. Mol. Can. Ther. 2012 , 11, 2265-2273

12. B) CDK9-Selective Inhibitors: 12 Compound R IC 50 (CDK9) IC 50 (CDK2) Aq. Solubility (pH= 7.4) 19 11 nM 1078 nM 11 mg L -1 20 13 nM 1300 nM 479 mg L -1 Compound X Y R 1 R 2 IC 50 (CDK9) IC 50 (CDK2) 21 N C F 37 nM 3959 nM 22 N C F 104 nM 10504 nM 23 C N F 4 nM 2920 nM Lücking, U. et al . Chem. Med. Chem. 2017, 12 , 1776-1793 https://clinicaltrials.gov/ct2/show/NCT02345382 (accessed Mar 2, 2021) Lücking , U. Org. Chem. Front. 2019 , 6 , 1319-1324 https://clinicaltrials.gov/ct2/show/NCT01938638 (accessed Mar 2, 2021)

13. 1.2) Ataxia Telangiectasia and Rad3 Related (ATR) Kinase Inhibitor: 13 Compound IC 50 ATR IC 50 ATR Cell Aqueous solubility pH = 7.4 24 5 nM 61 nM 10 µM 25 4 nM 74 nM 661 µM (R)-26 16 nM 180 nM 240 µM (S)-26 11 nM 90 nM 198 µM 27 5 nM 100 nM 8 µM 24 25 26 27 Foote, K . et al. J. Med. Chem. 2018 , 61 , 9889-9907 Foote, K . et al. Chem. Soc. Rev. 2019 , 48 , 5408-5423 Wiezorek , S. et al. J. Med. Chem. 2013 , 56 , 2125-2138

14. 1.3) Sulfoximine-based COX-2 Inhibitors 28 decrease hERG activity -31 COX-1 (69%), COX-2 (97%) 29 nonselective inhibitor -(R)-32 selective COX-2 inhibitor 97% 30 selective COX-2 inhibitor 48% 14 Compound R 28 29 30 Compound X 31 O 32 Marnett, L. et al . Trends Pharmacol. Sci. 1999, 20 , 465-469 Park, S. et al. Chem. Med. Chem. 2013 , 8 , 217-220

15. 2) Anti-infective agents: 2.1) Antimalarial agents: 2.2) Antibacterial agent: Sulfoximine-triazole Hybrid: Oxazolidinone-based sulfoximine: 15 IC 50 = 6.6 µM R 1 = H, alkyl, arylcarbamoyl, alkylurethanyl R 2 = (cyclo) alkyl Mabasa, T. et al. Med. Chem. 2019 , 15 , 685-692 Mäder, P . et al. ACS J. Med. Chem 2020 , 63, 23 , 14243-14275 33 34 Activity depend on long alkyl chain MIC Range 0.05-10 µg/mL

16. 3) Antidiabetic agents : 16 Compound R 1 R 2 IC 50 (DDP-4) 35 CH 3 H 34 nM 36 CH 3 37 nM 37 H 8.8 nM 38 H 18 nM Mäder, P . et al. ACS J. Med. Chem 2020, 63, 23 , 14243-14275 https://diabetesatlas.org/en/resources (accessed Mar 2, 2021) Dihydropyrrolepyrazoles as DPP-4 inhibitors Benzoyl group at sulfonyl urea nitrogen atom increases potency Sulphonimidamide moiety gave slightly less activity

17. 4) Antiretroviral Agents: sulfoximine-based antiretroviral agents: 17 Lu, D . et al. Bioorg. Med. Chem. 2010 , 18 , 2037-2048 Razza, A. et al. Bioorg. Med. Chem. Lett. 2008 , 18 , 5406-5410 IC 50 = 0.6 µM IC 50 = 100 µM HIV-1 protease inhibitor 39 40 41

18. 5) Agents for treatment of skin disease : ROR gamma inverse agonists : 18 Ouvry, G . et al. Bioorg. Med. Chem. Lett. 2018 , 28 , 1269-1273 https://clinicaltrials.gov/ct2/show/NCT03004846 (accessed Mar 2, 2021) IC 50 (ROR γ GAL4) = 17 Nm IC 50 (CD4 IL17) = 3.2 nM IC 50 (ROR γ GAL4) = 26 nM IC 50 (CD4 IL17) = 17 nM 42 43

19. 6) Agents for Treatment of Respiratory Diseases: sulfoximine-based hNE Inhibitors: 19 Mäder, P . et al. ACS J. Med. Chem 2020 , 63, 23 , 14243-14275 R 1 = Me, Et, iPr R 2 = Alkyl, (hetero) aryl R 3 = CF 3 , CHF 2 IC 50 <10 nM R = SO 2 CH 3 R = SO 2 CH 3 BAY858501 IC 50 = 0.065 nM R = S(O)(NH)CH 3 IC 50 = 0.250 nM 44 45 46 47

20. 7) CYP24 Hydroxylase Inhibitors: 20 Compound R IC 50 (CYP24A1) 48 - 49 28 nM 50 (24S) = 7.4 ± 4.2 nM (24R) = 28 ± 10 nM CTA-018, IC 50 = 27 ±6 nM Kahraman, M . et al. J. Med. Chem. 2004 , 47 , 6854-6863 Posner, G . et al. J. Med. Chem. 2000 , 43 , 3581- 3586 51

21. 8) Proline-Rich Tyrosine Kinase (PRTK) Inhibitor: 21 Compound R IC 50 PYK2 IC 50 PYK2 cell IC 50 FAK 53 95 nM 60 nM 1000 nM 54 140 nM 88 nM 1300 nM 55 65 nM 320 nM ND 56 (rac)-120: 67 nM (S)- 120: 43 nM (R)-120: 67 Nm (rac)-120: 76 nM (S)- 120: 29 nM (R)-120: 98 nM (rac)-120:1800 nM (S)- 120:1100 nM (R)-120:2300 nM 52 Walker, D. et al. Bioorg. Med. Chem. Lett. 2009 , 19 , 3253-3258

22. 9) Factor Xa Inhibitors: 22 Compound R 1 R 2 57 OMe 58 OMe 59 Cl 60 Cl 61 Cl Pandya, V. et al.Eur. J. Med. Chem. 2012 , 58 , 136-152

23. 1O) Bromodomain and Extra Terminal (BET) Inhibitors: Sulfoximine-based BET Inhibitors : 23 PFI-1 IC 50 (HEL) = 2.0 IC 50 (Molm-14) = 2.7 IC 50 (HEL) = 0.5 IC 50 (Molm-14) = 1.0 Altenberg, B. et al. ACS. Med. Chem. Lett.   2020 , 11 , 1928–1934 Mäder, P . et al. ACS J Med Chem 2020, 63 , 14243-14275 IC 50 (HEL) = 0.5 IC 50 (Molm-14) = 1.0 62 63 64

24. Summary & Conclusion Sulfoximine having a fine-tuning hydrogen bond acceptor and donor capability, chemical and metabolic stability, physicochemical properties Substitution pattern of Nitrogen and stereocenter of Sulfur atom incase of nonsymmetrical substitution the sulfoximine show structural diversity The sulfoximine compounds increasing numerous reports with properties as a rising acceptance of this class of compounds by medicinal chemist Sulfoximine group has been shown new role, in year 2019 at least four compound entered into clinical trials as a Sulfoximine-containing antineoplastic agent 24

25. 25 Thank You