A 1,3,4-thiadiazole library was constructed by solid-phase organic synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amido-5-amino-1,3,4-thiadiazole resin by the cyclization of thiosemicarbazide resin using p-TsCl as the desulfurative agent, followed by the functionalization of resin by alkylation, acylation, alkylation/acylation, and Suzuki coupling reaction. Both the alkylation and acylation reactions chemoselectively occurred at the 2-amide position of 2-amido-5-amino-1,3,4-thiadiazole resin and the 5-amine position of 2-amido-5-amino-1,3,4-thiadiazole resin, respectively. Finally, these functionalized 1,3,4-thiadiazole resins were treated with trifluoroacetic acid in dichloromethane, affording diverse 1,3,4-thiadiazole analogs in high yields and purities. The 1,3,4-thiadiazole analogs show different distribution of physicochemical and biological properties compared to our previously constructed 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries in a range of orally available drug properties.
KEYWORDS: Solid-phase, BOMBA, Thiosemicarbazide, 1,3,4-thiadiazole
Solid-phase synthesis has been emerged as a powerful tool in medicinal chemistry owing to its capability to rapidly generate massive number of small organic molecules.1 Among these small molecules, heterocyclic compounds are now considered as ideal scaffolds on which pharmacophores can be appended to yield potent and selective drugs.2 This is especially…