thioanalogues

Thioanalogues are chemical species in which a sulfur atom replaces a nonmetal atom—most commonly oxygen—in a parent compound. The substitution yields a thio analogue with altered electronic properties, bond lengths, and reactivity. The concept is widely used across organic chemistry, biochemistry, and medicinal chemistry to explore structure–activity relationships and to modulate properties such as lipophilicity and hydrolytic stability.

Common classes include thioesters (R-CO-S-R'), where the carbonyl oxygen is replaced by sulfur; thioamides (R-C(=S)-NR2), where the carbonyl oxygen is replaced by sulfur; and thioethers (R-S-R'), where oxygen in an ether is replaced by sulfur. In carbohydrate chemistry, substitution of ring oxygen with sulfur yields thioglycosides or thioacetals; similar substitutions occur in heterocycles such as thiazole-containing rings. Thio analogues can also refer to sulfur-containing surrogates of peptide or nucleobase motifs.

Synthesis commonly uses thionation reagents such as Lawesson's reagent or phosphorus pentasulfide to convert carbonyl groups to thiocarbonyls, or thiol- or sulfide-based routes to form thioethers. In glycoside chemistry, thioglycosyl donors enable the preparation of thioglycosides.

Applications include probing the role of oxygen in biological recognition, tuning metabolic stability, and adjusting physicochemical properties of drug candidates. In biology, thioesters such as acetyl-CoA are central metabolic intermediates; in medicinal chemistry, thioanalogues are evaluated as protease inhibitors and as mimics of natural functional groups.

Limitations and challenges include altered acidity, reactivity, and stability; sulfur-containing compounds can be more prone to oxidation and have different stereochemical preferences, complicating synthesis and handling. Nonetheless, thioanalogues provide valuable models for understanding structure–function relationships and for developing new materials and therapeutics.