Medicinal chemistry and properties of 1,2,4-thiadiazoles.
1,2,4-Thiadiazole is a distinctive class of small heterocyclic thiol trapping agents that serve as an interesting pharmacophore in the design of inhibitors targeting the cysteine residues of proteins. X-Ray crystal structures of enzyme-inhibitor complex indicate that the cysteine thiol reacts with the N-S bond of the thiadiazole moiety to form a disulfide bond resulting in the inactivation of the enzymes. This review addresses the medicinal chemistry and various properties of 1,2,4-thiadiazoles in their potential as new electrophilic "warheads" for targeting the cysteine residues of biomolecules (e.g, H+/K+ ATPase), and cysteine-dependent enzymes (e.g., cathepsin B and transglutaminase).
Tam
Tim Fat
TF
Apotex Research, Inc. Medicinal Chemistry Department, 400 Ormont Drive, Toronto, ON, M9L 1N9, Canada. ttam@apotex.com
Leung-Toung
Regis
R
Li
Wanren
W
Spino
Michael
M
Karimian
Khashayar
K
D002401:Cathepsin B / Q000737:chemistry / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry / Q000187:drug effects; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D011503:Transglutaminases / Q000737:chemistry / Q000187:drug effects
D004791:Enzyme Inhibitors; D013830:Thiadiazoles; D011503:Transglutaminases; D002401:Cathepsin B; D017506:H(+)-K(+)-Exchanging ATPase; D003545:Cysteine