Novel 5-(Arylideneamino)-1 H-Benzo[ d]imidazole-2-thiols as Potent Anti-Diabetic Agents: Synthesis, In Vitro α-Glucosidase Inhibition, and Molecular Docking Studies

Sardar Ali; Mumtaz Ali; Ajmal Khan; Saeed Ullah; Muhammad Waqas; Ahmed Al-Harrasi; Abdul Latif; Manzoor Ahmad; Muhammad Saadiq

doi:10.1021/acsomega.2c03854

Novel 5-(Arylideneamino)-1 H-Benzo[ d]imidazole-2-thiols as Potent Anti-Diabetic Agents: Synthesis, In Vitro α-Glucosidase Inhibition, and Molecular Docking Studies

ACS Omega. 2022 Nov 23;7(48):43468-43479. doi: 10.1021/acsomega.2c03854. eCollection 2022 Dec 6.

Authors

Sardar Ali¹, Mumtaz Ali¹, Ajmal Khan², Saeed Ullah^{2

3}, Muhammad Waqas^{2

4}, Ahmed Al-Harrasi², Abdul Latif¹, Manzoor Ahmad¹, Muhammad Saadiq⁵

Affiliations

¹ Department of Chemistry, University of Malakand, Dir Lower, Chakdara 18800 Khyber Pakhtunkhwa, Pakistan.
² Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Birkat Al Mauz, Nizwa 616, Oman.
³ H. E. J Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
⁴ Department of Biotechnology and Genetic Engineering, Hazara University, Mansehra 21120, Pakistan.
⁵ Department of Chemistry, Bacha Khan University, Charsadda 18800 Khyber Pakhtunkhwa, Pakistan.

Abstract

A novel series of multifunctional benzimidazoles has been reported as potent inhibitors of α-glucosidase. The procedure relies on the synthesis of 5-amino-1H-benzo[d]imidazole-2-thiol 5 via the multistep reaction through 2-nitroaniline 1, benzene-1,2-diamine 2, 1H-benzo[d]imidazole-2-thiol 3, and 5-nitro-1H-benzo[d]imidazole-2-thiol 4. Further treatment of 5 with aromatic aldehydes 6a-m provided access to the target 5-(arylideneamino)-1H-benzo[d]imidazole-2-thiols 7a-m. The results of the bioactivity assessment revealed all the compounds as excellent inhibitors of the enzyme (IC₅₀ range: 0.64 ± 0.05 μM to 343.10 ± 1.62 μM) than acarbose (873.34 ± 1.21). Among them, 7i was the most active inhibitor (IC₅₀: 0.64 ± 0.05 μM) followed by 7d (IC₅₀: 5.34 ± 0.16 μM), 7f (IC₅₀: 6.46 ± 0.30 μM), 7g (IC₅₀: 8.62 ± 0.19 μM), 7c (IC₅₀: 9.84 ± 0.08 μM), 7m (IC₅₀: 11.09 ± 0.79 μM), 7a (IC₅₀: 11.84 ± 0.26 μM), 7e (IC₅₀: 16.38 ± 0.53 μM), 7j (IC₅₀: 18.65 ± 0.74 μM), 7h (IC₅₀: 20.73 ± 0.59 μM), 7b (IC₅₀: 27.26 ± 0.30 μM), 7k (70.28 ± 1.52 μM) and finally 7l (IC₅₀: 343.10 ± 1.62 μM). Molecular docking revealed important interactions with the enzyme, thereby supporting the experimental findings.