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  • Initially the synthesized compounds from were evaluated for

    2021-11-29

    Initially, the synthesized compounds from were evaluated for human GSNOR potency before generating additional SAR in order to understand scaffold feasibility and Perhexiline maleate required functionality as illustrated in . Commercially available 4′-hydroxy-[1,1′-biphenyl]-4-carboxylic Perhexiline maleate having similar terminal functional groups as in N91115 () was tested for human GSNOR potency, which unveiled low GSNOR inhibition at 10 µM concentration. Next, imidazole derived carboxylic acid analog designed based on scaffold hopping strategy, afforded IC of 62 nM GSNOR potency which is roughly 4-fold lesser in comparison to clinical candidate N91115 (). Encouraged by this result, compound having tetrazole as a bioisostere replacement of carboxylic acid analog provided 3-fold enhanced GSNOR potency (IC: 22 nM) and is comparable to N91115 (). Tetrazole in compound was bioisosterically replaced with other groups, such as CN (), CONH () and 1,2,4-oxadiazol-5(2)-one () derived analogs unveiled substantial loss of potency. Similarly, bioisosteric replacement of imidazole in compound with CN (), C-tetrazole (), 1,3,4-triazole () and -tetrazole () derived analogs displayed inferior GSNOR potency (). Having identified optimum terminal A-ring (imidazole) and D-ring (tetrazole and or carboxylic acid) in the scaffold, additional compounds were synthesized by introducing various substituents and an insertion of nitrogen in B-, and C-rings with the purpose of improving GSNOR potency and physicochemical properties. Therefore, compounds –, –, –, – and were synthesized and tested for GSNOR potency as shown in , and , . Commercially available and meta-substituted 4-aminobenzonitriles and – were subjected to diazotization in the presence of NaNO and KI (Sandmeyer reaction) to afford 4-iodobenzonitrile derivatives and , and further Suzuki coupling with 4-bromophenylboronic acid provided biphenyl derivatives and – in 50–70% yield. Copper mediated coupling of and – with imidazole and 2-methylimidazole yielded imidazole derived biphenyls and – in 30–60% yield. Nitrile in compounds – and were hydrolyzed using aqueous sodium hydroxide to afford biphenylcarboxylic acid derivatives – in 60–80% yield. Further, nitrile compounds and were converted to tetrazole derivatives – using NaN in DMF at 100 °C (). Similarly, -substituted 4-bromoanilines and – were exposed to diazotization with NaNO/KI gave iodo derivatives and –, which was further subjected to Suzuki coupling with arylboronic acids , – to afford biphenyl derivatives and – in 40–70% yield. Compounds and – were reacted with imidazole and 2-methylimidazole in the presence of CuI to afford and , followed by tetrazole formation using NaN to give biphenyltetrazole derivatives – in >50% yield. Besides, biphenylcarboxylic acids and were prepared from the corresponding nitriles and using aqueous sodium hydroxide in 70–80% yield (). Subsequently, we also explored the synthesis of imidazole-biaryl-tetrazole derivatives having nitrogen incorporated in the B-ring in order to further improve potency and physicochemical properties as described in . Commercially available 3-substituted 2,5-dibromopyridines and – were coupled with various arylboronic acids and – in the presence of Pd(PPh) to afford 2-phenylpyridine derivatives and – in 40–70% yield. Copper catalyzed imidazole coupling of and – afforded compounds and – in 40–70% yield. Compounds and – were further converted to tetrazole derivatives – using NaN/EtNHCl in DMF to provide 60–80% yield. The carboxylic acid derivatives – were synthesized from the corresponding nitrile derivatives and – using aqueous sodium hydroxide in ethanol at 80 °C. Furthermore, nitro reduction of – gave amines and , followed by diazotization provided iodo-derivatives and in >50% yield over two steps. Sonogashira coupling of and with ethynyltrimethylsilane, followed by TMS-cleavage to afford and and further hydrogenation with Pd/C-H afforded compounds and . Reaction of nitrile derivatives and with NaN/EtN-HCl in DMF yielded tetrazole analogs and in 60% yield. Compound was prepared by Suzuki coupling of iodo derivative with cyclopropylboronic acid, followed by tetrazole formation with NaN afforded compound in 65% yield.