Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like PAR2 antagonist

[Display omitted] •Design of a new class of isoxazole-tethered diarylheptanoid analogs.•Stereo-conserved access to syn and anti-1,3-diol features starting from d-glucose.•Significantly improved in vitro drug-like properties compared to curcumin-I.•Structurally distinct and phytochemical based PAR2 antagonist scaffold.•Highlighted analog 4a with PAR2 IC50: 6 μM (HEK293 cells, trypsin agonist). A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3-syn-diol and 1,3-anti-diol chemophoric moieties, e.g. 4a–d and 5a–c respectively, have been designed and synthesized starting from d-glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve™ as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca2+]i release assay, 4a and 5a, when tested at 30 μM, inhibited the trypsin agonist induced protease-activated receptor-2 (PAR2) activity by 80% and 70% respectively. IC50 of 4a (SB70) has been determined as 6 μM which is in the same range of current benchmarks for PAR2 antagonists.