Thiazolylmethyl ortho-substituted phenyl glucoside library as novel C-aryl glucoside SGLT2 inhibitors

In order to investigate SAR regarding proximal phenyl ring in novel C-aryl glucoside SGLT2 inhibitors containing a thiazole motif, a series of chemical modifications on proximal phenyl ring was conducted. During a series of lead optimization efforts, ortho-allyloxyphenyl 10p or ortho-hydroxyphenyl 11a showed subnanomolar inhibitory activity against hSGLT2.

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► A new class of thiazole-substituted aryl glucosides was synthesized.
► High SGLT2 inhibitory activity was found for some glucosides, showing IC50 = 0.797 nM.
► This manuscript constitutes key synthetic methods to install alkoxy, alkyl, or halogen at the ortho-position at the proximal phenyl ring.