Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors

Abstract

Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-β-alanine 1,3,4-oxadiazole hybrids (4a–l), characterized by 1H- and 13C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-β-alanine 1,3,4-oxadiazole derivatives 4a–l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC50 value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II.

Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

“…Askin et al designed a protocol to synthesize new imidazole [2,1b] [1,3,4]thiadiazoles (73)(74)(75)(76)(77)(78)(79)(80)(81). Initially substituted benzyl chloride derivatives (62)(63)(64) were refluxed with KOH in presence of ethanol for 4-6 h to obtain 2-amino-1,3,4-thiadiazoles (66)(67)(68) Newly synthesized compounds were tested for their inhibitory activity against hCA I and hCA II by taking standard AAZ and THA and it was observed that compound 70b and 71 were found to be most potent against hCA I with K i values of 23.44 ± 4.92 and 51.53 ± 10.74 nM, respectively.…”

“…Newly synthesized compounds were screened for inhibitory activity against hCA II using colorimetric method by taking AAZ as standard drug and it was observed that all these derivatives except 412d (R = 4- Newly synthesized compounds were also subjected to molecular docking studies to determine binding affinity of compounds and it was observed that active compounds fitted perfectly in active site of CA II and formed hydrogen bond with Thr199, Thr200, Gln92 of CA II [75] (Scheme 56). All synthesized compounds were tested for in vitro inhibitory activity against hCA I, II, IX, and XII by taking AAZ as standard drug and it was observed that quinazoline compounds 414 (R = OCH 2 CH 3 ),…”

“…Newly synthesized compounds were also subjected to molecular docking studies to determine binding affinity of compounds and it was observed that active compounds fitted perfectly in active site of CA II and formed hydrogen bond with Thr199, Thr200, Gln92 of CA II [ 75 ] (Scheme 56).…”

Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H,5H-pyrano[3,2-c]chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors

“…Some of the selected compounds from the literature − are reported here in Figure as hCA II and β-glucuronidase inhibitors, which are rationalized with current work to disclose their metabolic liabilities and/or biological potencies.…”

Designing Next-Generation Drug-like Molecules for Medicinal Applications

“…The structures were fully established through various spectroscopic methods. The carbonic anhydrase inhibitory profile was examined and the acquired in vitro efficacy was remarkable, which was further validated with computational modeling analysis [ 11 ].…”