Synthesis of New 1 H-1,2,3-Triazole Analogs in Aqueous Medium via " Click" Chemistry: A Novel Class of Potential Carbonic Anhydrase-II Inhibitors

Abstract

A series of novel 1H-1,2,3-triazole analogs (9a-j) were synthesized via "Click" chemistry and Suzuki-Miyaura cross-coupling reaction in aqueous medium. The compounds were evaluated for their carbonic anhydrase-II enzyme inhibitory activity in vitro. The synthesis of triazole 7a was accomplished using (S)-(-) ethyl lactate as a starting material. This compound (7a) underwent Suzuki-Miyaura cross-coupling reaction with different arylboronic acids in aqueous medium to afford the target molecules, 9a-j in good yields. All newly synthesized compounds were characterized by ¹H NMR, ¹³C NMR, FT-IR, HRMS, and where applicable ¹⁹F NMR spectroscopy (9b, 9e, 9h, and 9j). The new compounds have shown moderate inhibition potential against carbonic anhydrase-II enzyme. A preliminary structure-activity relationship suggested that the presence of polar group at the 1H-1,2,3-triazole substituted phenyl ring in these derivatives (9a-j) has contributed to the overall activity of these compounds. Furthermore, via molecular docking, it was deduced that the compounds exhibit inhibitory potential through direct binding with the active site residues of carbonic anhydrase-II enzyme. This study has unraveled a new series of triazole derivatives as good inhibitors against carbonic anhydrase-II.

Keywords: 1H-1, 2, 3-triazole analogs; aqueous medium; carbonic anhydrase-II inhibitory activity; click chemistry; molecular docking studies; synthesis.

FIGURE 1

(A) Chemical structures of some clinically used 1H-1,2,3-triazole analogs as potential carbonic anhydrase-II inhibitors. (B) Chemical structures of surinamensinols A and B.

SCHEME 1

Reagents and conditions: (A) 4-bromo-2-methoxyphenol, PPh₃, DIAD, dry THF, 0°C to room temperature, 3 h, 86%; (B) DIBAL-H, dry DCM, 0°C to room temperature, 3 h, 90%; (C) TsCl, Et₃N, dry DCM, DMAP, 0°C to room temperature, 5 h, 95%; (D) NaN₃, DMF, 70°C, 3 h, 78%; (E) alkyne derivative (6a–b), CuI, Et₃N, MeCN, room temperature, 3 h, 7a (76%) and 7b (82%).

SCHEME 2

Synthesis of 9a–j. Reagents and conditions: (i) 7a (1.0 equiv), 8a–j (1.2–1.5 equiv), Pd(OAc)₂ (5 mol%), K₂CO₃ (3.0 equiv), THF:H₂O (3 : 1), 80–85°C 10–12 h (82–91%).

FIGURE 2

General structural feature of the synthesized molecules (9).

FIGURE 3

(A) The active site of the carbonic anhydrase is shown. (B) The binding mode of the most active compound (7b) within the active site of carbonic anhydrase. Ligand is presented as a light pink stick model and hydrogen bonds are shown in black lines. (C) The docked poses of all active ligands in the active site of the bovine carbonic anhydrase.

FIGURE 4

(A) The binding mode of the standard inhibitor “acetazolamide (AZM)” in the active site of CA-II in the 3D form. H-bond and metal-ligand interaction are shown in black lines. (B) The protein-ligand interaction is shown in 2D form. The H-bond and metal-ligand interaction are displayed in blue and magenta dotted lines, respectively.