Synthesis and In Silico Analysis of New Polyheterocyclic Molecules Derived from [1,4]-Benzoxazin-3-one and Their Inhibitory Effect against Pancreatic α-Amylase and Intestinal α-Glucosidase
Mohamed Ellouz,
Aziz Ihammi,
Abdellah Baraich,
Ayoub Farihi,
Darifa Addichi,
Saliha Loughmari,
Nada Kheira Sebbar,
Mohamed Bouhrim,
Ramzi A. Mothana,
Omar M. Noman,
Bruno Eto,
Fatiha Chigr,
Mohammed Chigr
Affiliations
Mohamed Ellouz
Laboratory of Molecular Chemistry, Materials and Catalysis (LCMMC), Faculty of Sciences and Technology, Sultan Moulay Slimane University, P.O. Box 523, Beni-Mellal 23000, Morocco
Aziz Ihammi
Laboratory of Molecular Chemistry, Materials and Catalysis (LCMMC), Faculty of Sciences and Technology, Sultan Moulay Slimane University, P.O. Box 523, Beni-Mellal 23000, Morocco
Abdellah Baraich
Laboratory of Bioresources, Biotechnology, Ethnopharmacology and Health, Faculty of Sciences, Mohammed First University, Boulevard Mohamed VI, P.O. Box 717, Oujda 60000, Morocco
Ayoub Farihi
Laboratory of Biology and Health, Faculty of Sciences, Ibn Tofail University, Kenitra 14000, Morocco
Darifa Addichi
Laboratory of Molecular Chemistry, Materials and Catalysis (LCMMC), Faculty of Sciences and Technology, Sultan Moulay Slimane University, P.O. Box 523, Beni-Mellal 23000, Morocco
Saliha Loughmari
Laboratory of Molecular Chemistry, Materials and Catalysis (LCMMC), Faculty of Sciences and Technology, Sultan Moulay Slimane University, P.O. Box 523, Beni-Mellal 23000, Morocco
Nada Kheira Sebbar
Laboratory of Organic and Physical Chemistry, Applied Bioorganic Chemistry Team, Faculty of Sciences, Ibnou Zohr University, Agadir 80000, Morocco
Mohamed Bouhrim
Biological Engineering Laboratory, Faculty of Sciences and Techniques, Sultan Moulay Slimane University, Beni Mellal 23000, Morocco
Ramzi A. Mothana
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
Omar M. Noman
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
Bruno Eto
Laboratoires TBC, Laboratory of Pharmacology, Pharmacokinetics, and Clinical Pharmacy, Faculty of Pharmaceutical and Biological Sciences, P.O. Box 83, F-59000 Lille, France
Fatiha Chigr
Biological Engineering Laboratory, Faculty of Sciences and Techniques, Sultan Moulay Slimane University, Beni Mellal 23000, Morocco
Mohammed Chigr
Laboratory of Molecular Chemistry, Materials and Catalysis (LCMMC), Faculty of Sciences and Technology, Sultan Moulay Slimane University, P.O. Box 523, Beni-Mellal 23000, Morocco
This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a–5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a “click chemistry” approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of −9.9 and −9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski’s criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development.
