Application of Sulfonyl in Drug Design

Abstract

Sulfonyl-containing compounds comprise a substantial proportion in the therapeutic drugs. It is an important strategy to introduce sulfonyl group into the small molecules for structure-based medicinal chemistry, the application of sulfonyl group in drug design is reviewed in this paper. Structurally, sulfonyl group has similar properties in molecular size and charge distribution with carbonyl, carboxyl, tetrazolium and phosphate group, so it can be introduced into the drug molecules as their bioisostere in order to remain or improve activity. Sulfonyl group possesses unique physicochemical properties, and the introduction of sulfonyl group can also modulate the solubility and acid-base property of the drug molecules. Sulfonyl group can offer two hydrogen-bond receptors, and reasonable introduction of sulfonyl group can enhance the binding affinity of the drug molecules with the targeted proteins to improve activity through hydrogen bond interactions. What's more, sulfonyl group is relatively stable in terms of structure, the introduction of sulfonyl group can increase the metabolic stability of drugs to prolong the duration of action by blocking metabolically labile sites, improve the pharmacokinetic properties of the drug molecules to elevate the bioavailability. Sulfonyl group belongs to polar groups, which can also increase the polarity of the drug molecules to diminish hERG activity.

Dual gold and photoredox catalysis: visible light-mediated intermolecular atom transfer thiosulfonylation of alkenes

“… 7 Sulfonyl groups are similar to carboxyl or phosphate groups in terms of molecular size and charge distribution, and the sulfonyl group has been introduced into bioactive molecules to improve their activity. 8 A sulfonyl group has two receptors for hydrogen bonds and this can enhance the binding affinities of drug molecules with target proteins. Sulfones can be easily transformed into other functional groups, such as alkenes, via Julia olefination.…”

Enantioselective Synthesis of α-Aryl-β-Aminocyclopropane Carboxylic Acid Derivatives via Rh(II)-Catalyzed Cyclopropanation of Vinylsulfonamides with α-Aryldiazoesters

“…Interestingly, for substrates bearing either one N -electron-withdrawing group ( 2q – r ) or two N -Boc-protected groups ( 2s ), there is no reaction at all under the standard reaction conditions, while the corresponding product 3at was smoothly obtained in high yield with excellent stereocontrol for vinylamide 2t bearing two N -electron-withdrawing carbonyl groups. These results showed that vinylsulfonamides have complementary advantages over vinylamides/vinylcarbamates for the Rh­(II)-catalyzed cyclopropanation reaction and could also offer potential applications in pharmaceutical chemistry for bioisosteric replacement of carbonyl groups …”

Design, Synthesis and Fungicidal Activity of 2-Substituted Phenyl-2-oxo-, 2-Hydroxy- and 2-Acyloxyethylsulfonamides

“…The sulfonyl group is widely applied in the field of functional organic molecule design due to its stable structure and high polarity with strong electron withdrawing ability. Sulfonyl groups can supply two hydrogen-bond acceptors, and a monosubstituted sulfonamide can supply an additional hydrogen-bond donor [ 6 ]. Structurally, the sulfonyl group possesses similar molecular size and charge distribution properties as carbonyl, carboxyl and phosphate groups, which can be replaced by a sulfonyl group as a bioisostere to retain or improve bioactivity [ 7 , 8 , 9 ].…”