Exploring Probenecid Derived 1,3,4-Oxadiazole-Phthalimide Hybrid as α-Amylase Inhibitor: Synthesis, Structural Investigation, and Molecular Modeling

Bilal Ahmad Khan; Syeda Shamila Hamdani; Muhammad Khalid; Muhammad Ashfaq; Khurram Shahzad Munawar; Muhammad Nawaz Tahir; Ataualpa A C Braga; Ahmed M Shawky; Alaa M Alqahtani; Mohammed A S Abourehab; Gamal A Gabr; Mahmoud A A Ibrahim; Peter A Sidhom

doi:10.3390/ph16030424

Exploring Probenecid Derived 1,3,4-Oxadiazole-Phthalimide Hybrid as α-Amylase Inhibitor: Synthesis, Structural Investigation, and Molecular Modeling

Pharmaceuticals (Basel). 2023 Mar 10;16(3):424. doi: 10.3390/ph16030424.

Authors

Bilal Ahmad Khan¹, Syeda Shamila Hamdani¹, Muhammad Khalid^{2

3}, Muhammad Ashfaq⁴, Khurram Shahzad Munawar^{5

6}, Muhammad Nawaz Tahir⁴, Ataualpa A C Braga⁷, Ahmed M Shawky⁸, Alaa M Alqahtani⁹, Mohammed A S Abourehab¹⁰, Gamal A Gabr^{11

12}, Mahmoud A A Ibrahim^{13

14}, Peter A Sidhom¹⁵

Affiliations

¹ Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad 13100, Pakistan.
² Institute of Chemistry, Khwaja Fareed University of Engineering & Information Technology, Rahim Yar Khan 64200, Pakistan.
³ Centre for Theoretical and Computational Research, Khwaja Fareed University of Engineering & Information Technology, Rahim Yar Khan 64200, Pakistan.
⁴ Department of Physics, University of Sargodha, Punjab 40100, Pakistan.
⁵ Institute of Chemistry, University of Sargodha, Sargodha 40100, Pakistan.
⁶ Department of Chemistry, University of Mianwali, Mianwali 42200, Pakistan.
⁷ Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo 05508-000, Brazil.
⁸ Science and Technology Unit (STU), Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁹ Pharmaceutical Chemistry Department, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
¹⁰ Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
¹¹ Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
¹² Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza 12619, Egypt.
¹³ Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt.
¹⁴ School of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.
¹⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.

Abstract

1,3,4-Oxadiazole moiety is a crucial pharmacophore in many biologically active compounds. In a typical synthesis, probenecid was subjected to a sequence of reactions to obtain a 1,3,4-oxadiazole-phthalimide hybrid (PESMP) in high yields. The NMR (¹H and ¹³C) spectroscopic analysis initially confirmed the structure of PESMP. Further spectral aspects were validated based on a single-crystal XRD analysis. Experimental findings were confirmed afterwards by executing a Hirshfeld surface (HS) analysis and quantum mechanical computations. The HS analysis showed the role of the π⋯π stacking interactions in PESMP. PESMP was found to have a high stability and lower reactivity in terms of global reactivity parameters. α-Amylase inhibition studies revealed that the PESMP was a good inhibitor of α-amylase with an s value of 10.60 ± 0.16 μg/mL compared with that of standard acarbose (IC₅₀ = 8.80 ± 0.21 μg/mL). Molecular docking was also utilized to reveal the binding pose and features of PESMP against the α-amylase enzyme. Via docking computations, the high potency of PESMP and acarbose towards the α-amylase enzyme was unveiled and confirmed by docking scores of -7.4 and -9.4 kcal/mol, respectively. These findings shine a new light on the potential of PESMP compounds as α-amylase inhibitors.

Keywords: DFT calculations; X-ray diffraction; molecular docking; oxadiazole; α-amylase inhibition.

Abstract

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