New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

Abstract

Extension of the medicinal chemistry toolbox is in the vital interest of drug designers. However, the diffusion of an innovation can be a lengthy process. Along these lines, it took almost 70 years before the use of the sulfoximine group reached a critical mass in medicinal chemistry. Even though interest in this versatile functional group has increased exponentially in recent years, there is ample room for further innovative applications. This Review highlights emerging trends and opportunities for drug designers for the utilization of the sulfoximine group in medicinal chemistry, such as in the construction of complex molecules, proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and novel warheads for covalent inhibition.

Applications of Bioisosteres in the Design of Biologically Active Compounds

“…The sulfoximine moiety offers interesting properties, with a chiral, hydrophilic core that can accept H-bonds via the oxygen or nitrogen atoms, while N–H sulfoximines present an H-bond donor. The functionality was originally discovered with methionine sulfoximine ( 112 ), which was identified as the principle from NCl 3 -treated flour associated with causing convulsions. − The mode of action was traced to the N -phosphorylated metabolite 113 , which is formed in vivo where it functions as a glutamate mimetic. The properties of the sulfoximine functionality have attracted the interest of medicinal chemists with an interesting periodicity. − Early sulfoximine-containing drug candidates include suloxifen ( 114 ), which advanced into clinical trials in the 1970s as a spasmolytic and antiasthmatic agent, and sudexanox ( 115 ), which is an antiallergy agent studied clinically in the 1980s. − The design of 115 explored the potential of the N -unsubstituted sulfoximine moiety to function as a bioisostere of a CO 2 H substituent in the context of the pharmacophore inherent to disodium cromoglycate ( 116 , DSCG).…”

Synthesis of Sulfoximines and Sulfonimidamides Using Hypervalent Iodine Mediated NH Transfer

“…Subsequently, sulfoximine-containing compounds entered the clinic, including BAY 1143572, a PTEFb inhibitor, also from Bayer [ 11 , 12 ], and ceralasertib (AZD6738) an ATR kinase inhibitor from AstraZeneca ( Figure 1 ) [ 13 , 14 , 15 ]. An increasing number of sulfoximine-containing bioactive compounds are now appearing in the literature as the sulfoximine group is both increasingly established and increasingly accessible [ 16 , 17 ], and drug discovery applications were recently reviewed [ 18 , 19 , 20 , 21 ]. Sulfonimidamides are less progressed in drug discovery programs, but also offer considerable promise in medicinal and agrochemical applications [ 22 , 23 , 24 , 25 ].…”

Visible-Light-Induced One-Pot Cross Coupling of NH-Sulfoximines with Toluene

“…Due to their chiral sulfur center and ability to coordinate with metal ions, sulfoximines were mainly used as chiral auxiliaries or ligands in asymmetric reactions or catalysis in the early years . In recent years, as the application of organic sulfur compounds in pharmaceuticals has attracted more and more attention, people have also realized the potential application value of sulfoximines in pharmaceutical and pesticide industry. At present, several drugs containing sulfoximine groups, such as atuveciclib, BAY1251152, and AZD6738, have entered the clinical trial stage .…”