Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India.
Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
Bioorg Chem. 2020 May;98:103739. doi: 10.1016/j.bioorg.2020.103739. Epub 2020 Mar 10.
A series of coumarin linked 1,2,4-oxadiazoles were synthesized and the synthesized compounds were subjected for evaluation against the four physiologically and pharmacologically relevant hCA isoforms, hCA I, II, IX and XII. Upon evaluation of the results, it was inferred that the coumarin linked 1,2,4-oxadiazoles showed selective hCA IX and XII inhibition (low to medium nanomolar range) over hCA I and II (>10000 nM). The inhibition constants ranged from low nanomolar to moderately nanomolar. Compounds 6o, 6a, 6q and 6c elicited hCA XII inhibition, with K values lower than that of the standard, Acetazolamide (AAZ) with compound 6o exhibiting a K value of 1 nM., against hCA IX, the compound 6c exhibited the most potent inhibition with a K value of 23.6 nM. Hence, compound 6o can be taken as an effective lead compound for the development of hCA XII inhibitors and compound 6c can be taken as a lead compound for the development of dual hCA IX and XII inhibitors. To understand the molecular interactions, the two most potent compounds 6a and 6o were docked within the hCA XII catalytic cleft in order to study their binding modes with that isoform.
一系列香豆素连接的 1,2,4-噁二唑被合成，并对合成的化合物进行了评估，以对抗四种生理和药理学上相关的 hCA 同工酶，即 hCA I、II、IX 和 XII。在评估结果后，推断香豆素连接的 1,2,4-噁二唑对 hCA IX 和 XII 具有选择性抑制作用（低至中纳摩尔范围），而对 hCA I 和 II 的抑制作用较弱（>10000nM）。抑制常数范围从低纳摩尔到中等纳摩尔。化合物 6o、6a、6q 和 6c 对 hCA XII 具有抑制作用，其 K 值低于标准物乙酰唑胺（AAZ），化合物 6o 的 K 值为 1nM。对于 hCA IX，化合物 6c 表现出最有效的抑制作用，其 K 值为 23.6nM。因此，化合物 6o 可作为开发 hCA XII 抑制剂的有效先导化合物，化合物 6c 可作为开发双重 hCA IX 和 XII 抑制剂的先导化合物。为了了解分子相互作用，将两个最有效的化合物 6a 和 6o 对接在 hCA XII 的催化裂缝内，以研究它们与该同工酶的结合模式。
