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  • As a part of our continuing efforts towards discovery

    2022-01-14

    As a part of our continuing efforts towards discovery of new class of compounds against different therapeutic areas and based on the literature reports, we designed a dual pharmacophore which possess a long aliphatic chain of free fatty acids and a phenyl propanoid part of known GPR40 agonists. Herein, we report synthesis of several diacylphloroglucinol compounds using simple synthetic strategy and evaluation of these compounds for GPR40 agonistic activity. Series of diacyl phloroglucinol compounds were synthesized starting from commercially available phloroglucinol () by varying acyl functionality. Phloroglucinol () on treatment with isovaleric Teriflunomide in presence of boron trifluoride etherate under reflux for 2h resulted in formation of phloroisovalerophenone () and 2,4-diisovaleryl phloroglucinol () in 90% (30:70–mono:di) yield. Compound was further treated with formaldehyde solution in dichloromethane at 60°C for 8–10h resulting in formation of dimer in 85% yield (). Phloroglucinol () on treatment with chloroacetyl chloride in presence of AlCl in nitrobenzene led to formation of desired 2,4-di-(chloroacetyl) phloroglucinol () in 50% yield. Further, several diacyl phloroglucinol compounds were synthesized using different short to long-chain fatty acids. Treatment of phloroglucinol () with isobutyric acid, caprylic acid, lauric acid, stearic acid and palmitic acid in presence of boron trifluoride etherate under reflux for 2h resulted in formation of desired diacyl phloroglucinol compounds – in 50–75% yield (). Compound was earlier reported in literature as an antagonist of thromboxane A2 and Leukotriene D4. In order to develop structure–activity relationship, O- and C-alkylated analogues – of 2,4-diisovaleryl phloroglucinol () were synthesized (). Treatment of with -butyl bromide in presence of potassium carbonate in acetone at room temperature for 10h resulted in formation of three products – in 50% yield (ratio of ::=50:30:20). Compound was synthesized by refluxing with -butyl bromide in presence of freshly prepared sodium methoxide for 2h. Further, analogues with terminal carboxylic acid group on acyl chain ( and ) were synthesized in order to study the effect of negatively charged functionality on GPR40 agonistic activity. Compounds and were synthesized by treatment of or with glutaric anhydride in presence of BF etherate at room temperature for 2h in 40–45% yield. However, under similar reaction conditions, when phloroglucinol () was treated with succinic anhydride in presence of BF etherate, desired product with terminal carboxylic acid group was not formed; instead a condensed product was obtained. Further, a hydroxyethyl substituted analogue was synthesized by reaction of with bromoethanol in presence of potassium carbonate in acetone at room temperature for 10h in 50% yield. Synthesis of analogues – is depicted in . All compounds were evaluated for GPR40 agonistic activity using a functional calcium-flux assay., Linoleic acid was used as a standard GPR40 agonist. The agonist activity was measured as the fold increase of calcium flux over control in CHO cells expressing the hGPR40 vector using the Flex Station. The activity of all compounds was compared with that of linoleic acid. Linoleic acid exhibited GPR40 agonism with an EC of 0.54μM. Previously, Itoh et al. have reported comparable calcium flux response in the FLIPR for linoleic acid (EC=1.8μM) with similarly hGPR40 transfected CHO cells. Out of the 17 compounds tested, compounds , , and showed good agonistic activity at 10μM (). Specificity of compounds for GPR40 was confirmed by running parallel Ca flux assay in CHO cells with the vector lacking the hGPR40 transfection. From results (), it was noticed that substitution of phenolic hydroxyls with alkyls (–) resulted in loss of activity while alkylation on aromatic ring () did not alter GPR40 agonistic potential. Dimerization (compound ) of active compound resulted in loss of activity. Analogues with terminal carboxylic acid group on acyl chain ( and ) did not showed GPR40 agonistic activity. As well as hydroxyethyl substituted analogue was inactive.