Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adıyaman University, Adıyaman, 02040, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, 24002, Turkey.
Arch Biochem Biophys. 2024 Nov;761:110181. doi: 10.1016/j.abb.2024.110181. Epub 2024 Oct 11.
Sulfonamides, recognized as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, are crucial in treating diverse diseases, including epilepsy, glaucoma, bacterial infections, and various pathological processes, e.g., high blood pressure, rheumatoid arthritis, ulcerative colitis, pain, and inflammation. Additionally, therapeutically, 1,3-diaryl-substituted triazenes and sulphamethazines (SM) are integral components in various drug structures, and the synthesis of novel compounds within these two categories holds substantial significance. Herein, ten 1,3-diaryltriazene-substituted sulphamethazine derivatives SM(1-10), which were created by reacting the diazonium salt of sulphamethazine with substituted aromatic amines, were synthesized and the physiologically and pharmacologically relevant human (h) isoforms hCA I and II, cytosolic isozymes, were included in the study. The synthesized compounds showed excellent inhibition versus hCAs; the 4-butoxy (SM7, K of 5.69 ± 0.59 nM) compound exhibited a potent inhibitory effect against the hCA I compared with the reference drug acetazolamide (AAZ, K of 116.00 ± 8.48 nM). The 4-cyano (SM4, K of 5.87 ± 0.57 nM) compound displayed higher potency than AAZ (K of 57.25 ± 4.15 nM) towards hCA II. Meanwhile, among the synthesized molecules, the 3,4-dimethoxy (SM9, K of 74.98 ± 10.49 nM, S of 9.94) compound (over hCA I) displayed a noticeable selectivity for hCA isoform II. The target compounds in the molecular docking investigation were determined to take part in various hydrophilic and hydrophobic interactions with nearby amino acids and fit nicely into the active sites of the hCAs. This research has yielded compounds displaying varying affinity toward hCA isoenzymes, ultimately serving as potent and selective hCA inhibitors. Given its substantial biological inhibitory potency, this particular derivative series is determined to hold the potential to serve as a promising lead compound against these hCAs.
磺胺类药物被认为是碳酸酐酶（CA，EC 4.2.1.1）抑制剂，在治疗各种疾病方面起着至关重要的作用，包括癫痫、青光眼、细菌感染以及各种病理过程，如高血压、类风湿性关节炎、溃疡性结肠炎、疼痛和炎症。此外，在治疗方面，1,3-二芳基取代的三氮烯和磺胺类药物（SM）是各种药物结构中的重要组成部分，这两类化合物的新型化合物的合成具有重要意义。在此，通过将磺胺的重氮盐与取代的芳族胺反应，合成了十个 1,3-二芳基三氮烯取代的磺胺类药物衍生物 SM（1-10），并包括了与生理和药理相关的人（h）同工型 hCA I 和 II、胞质同工型。合成的化合物对 hCAs 表现出优异的抑制作用；与参比药物乙酰唑胺（AAZ，K 值为 116.00 ± 8.48 nM）相比，具有 4-丁氧基（SM7，K 值为 5.69 ± 0.59 nM）的化合物对 hCA I 具有更强的抑制作用。具有 4-氰基（SM4，K 值为 5.87 ± 0.57 nM）的化合物对 hCA II 的活性比 AAZ（K 值为 57.25 ± 4.15 nM）更高。同时，在所合成的分子中，具有 3,4-二甲氧基（SM9，K 值为 74.98 ± 10.49 nM，S 值为 9.94）的化合物（对 hCA I）对 hCA 同工型 II 表现出明显的选择性。分子对接研究中的靶化合物被确定与附近的氨基酸参与各种亲水和疏水相互作用，并很好地适合 hCA 的活性部位。这项研究产生了对 hCA 同工酶具有不同亲和力的化合物，最终成为有效的和选择性的 hCA 抑制剂。鉴于其具有很强的生物抑制活性，这个特定的衍生物系列被认为有可能成为针对这些 hCA 的有前途的先导化合物。
