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    • The Type A series contains of

    2022-11-09

    The Type-A series contains 6 of the 11 confirmed hits, making it a highly attractive lead template. Seven (7) out of 8 Type-A series of 3-substituted-2-furoic acids are highly active (84–100% inhibition) at the high concentration of 100μM. We could deduce some interesting, albeit preliminary structure-activity relationship (SAR) findings based on the % inhibition at 10μM. Largely speaking, compounds (A6-8) with the R/R-fused aromatic tricyclic 2-chromenone moieties are less potent than their 2-chromenone analogs (A1-4). The -propyl group (R) at the 6-positon of the 2-chromenone moiety seemed to be optimal for its activity (A1). Its replacement by a proton in analog A2 or the -hexyl group in A4 leads to reduced activity. Compound A5, which contains a greasy -hexyl group (R) and the fused tricyclic cyclohexo-2-chromenone, is one of the most potent compounds of the series (95% inhibition at 10μM). In addition, the closely related isomeric 5-substituted-2-furoic Vitamin D3 B1 is an active inhibitor (88% inhibition at 100μM), and only barely missed our hit selection criteria (18% inhibition at 10μM vs. 20% inhibition required). From the 11 Type-C benzofuran compounds, we can identify certain SAR trends in inhibitory activity of ACL. In general, the naphtho[1,2-]furans seem to be more active than the benzofurans (C5-11) in Type-C benzofuran derivatives. Among the 4 naphtho[1,2-]furans (C1–C4), their activity seems to be sensitive to the substitution at the 4-position (R) of the phenylsulfonyl moiety, demonstrating the following order of activity: Et>F>Me∼-Bu. Similarly, benzofurans C5-11 with a methyl or fluoro group at the 4-position (R) of the phenylsulfonyl moiety (C7-9) show increased potency over compound C5 in which R is a hydrogen atom. In addition, a methyl group at 2-position (R) of the phenylsulfonyl moiety in benzofurans is detrimental to the activity (C11 and C6). Finally, the benzofuran derivative with an either linker to the aryl group on the left side (D1) also showed good ACL inhibitory activity, which suggests that the sulfonamide liker in Type-C could be replaced during lead optimizations. The calculated LogP (cLogP) value of all compounds was generated by using the weighted methodology in the Marvin ChemAxom software package (V14.8.18.0). The cLogP of the 11 confirmed hits ranges from 3.5 to 6.0. The cLogP of the remaining compounds ranges from 3.0 to 5.1, with the exception of compound C11 (cLogP: 1.4), in which a methylsulphonyl group replaces the phenylsulfonyl moiety of C1-10. It is worth noting that compound C11 still showed modest activity (72% inhibition at 100μM). The high lipophilicity of A4 and A5 is mainly due to the presence of a grassy -hexyl chain that does not seem to be a structural component critical to activity; and we can identify the tetrafluorophenyl group in D1 for its high cLogP value. The cLogP for all other compounds is less than or close to 5, within the consideration of drug-like characteristics., Next, we determined the IC of A1, A3, and C4 in a dose-dependent ACL enzymatic assay, and included BMS-303141 as a positive control (). We selected these three confirmed hits mainly because of their moderate cLogP as well as structural uniqueness. The dose response results correlate well with the initial two-concentration screening. With an IC of 4.1μM, A1 is the most potent ACL inhibitor among all the furoic acids. A3 and C4, with IC at 11.9 and 13.8μM, respectively, are about equally active. In comparison, the IC of the optimized lead BMS-303141 is 0.377μM in the same assay, about 11 folds more active than the furoic screening hit A1. Shown in are the docking poses for inhibitors C4 and A1 in the CBD and the allosteric binding domain of the ACL structure. The carboxyl group of C4 is positioned deep inside the CBD and forms H-bond interactions with Asn346, Phe347 and Thr348. The phenyl moiety of C4 participates in hydrophobic interactions with the side chains of Phe347 and Ile597, which in part form the allosteric hydrophobic domain of ACL (A). For inhibitor A1 the carboxyl group and the ether bridge form H-bond interactions with Ser343 and Gly309, respectively. The carboxyl group is also within proximity of the side chain of Arg379 to form a salt bridge. In addition, hydrophobic interactions between the side chain of Phe347 and the furan and chromenone moieties also contributed to the stabilization of the A1-ACL complex (B).