Multifunctional Derivatives of Spiropyrrolidine Tethered Indeno-Quinoxaline Heterocyclic Hybrids as Potent Antimicrobial, Antioxidant and Antidiabetic Agents: Design, Synthesis, In Vitro and In Silico Approaches

Nouha Bouali; Manel Ben Hammouda; Iqrar Ahmad; Siwar Ghannay; Amira Thouri; Amal Dbeibia; Harun Patel; Walid Sabri Hamadou; Karim Hosni; Mejdi Snoussi; Mohd Adnan; Md Imtaiyaz Hassan; Emira Noumi; Kaïss Aouadi; Adel Kadri

doi:10.3390/molecules27217248

Multifunctional Derivatives of Spiropyrrolidine Tethered Indeno-Quinoxaline Heterocyclic Hybrids as Potent Antimicrobial, Antioxidant and Antidiabetic Agents: Design, Synthesis, In Vitro and In Silico Approaches

Molecules. 2022 Oct 25;27(21):7248. doi: 10.3390/molecules27217248.

Authors

Nouha Bouali¹, Manel Ben Hammouda², Iqrar Ahmad³, Siwar Ghannay⁴, Amira Thouri⁵, Amal Dbeibia⁶, Harun Patel³, Walid Sabri Hamadou¹, Karim Hosni⁷, Mejdi Snoussi^{1

8}, Mohd Adnan¹, Md Imtaiyaz Hassan⁹, Emira Noumi¹, Kaïss Aouadi^{4

10}, Adel Kadri^{11

12}

Affiliations

¹ Department of Biology, College of Science, Hail University, P.O. Box 2440, Hail 2440, Saudi Arabia.
² Laboratory of Heterocyclic Chemistry Natural Product and Reactivity/CHPNR, Department of Chemistry, Faculty of Science of Monastir, University of Monastir, Monastir 5000, Tunisia.
³ Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India.
⁴ Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia.
⁵ Laboratory of Bioresources, Biology Integrative and Valorization, Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir 5000, Tunisia.
⁶ Laboratory of Analyzes, Treatment and Valorization of Environmental Pollutants and Products, Faculty of Pharmacy of Monastir, University of Monastir, Monastir 5019, Tunisia.
⁷ Laboratoire des Substances Naturelles, Institute National de Recherche et d'Analyse Physico-Chimique, Biotechpôle de Sidi Thabet, Sidi Thabet 2020, Tunisia.
⁸ Laboratory of Genetics, Biodiversity and Valorization of Bio-Resources (LR11ES41), Higher Institute of Biotechnology of Monastir, University of Monastir, Avenue Tahar Haddad, BP74, Monastir 5000, Tunisia.
⁹ Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
¹⁰ Department of Chemistry, Faculty of Science of Monastir, University of Monastir, Avenue of the Environment, Monastir 5019, Tunisia.
¹¹ Department of Chemistry, Faculty of Science and Arts of Baljurashi, Albaha University, Al Bahah P.O. Box 1988, Saudi Arabia.
¹² Department of Chemistry, Faculty of Science of Sfax, University of Sfax, B.P. 1171, Sfax 3000, Tunisia.

Abstract

To combat emerging antimicrobial-resistant microbes, there is an urgent need to develop new antimicrobials with better therapeutic profiles. For this, a series of 13 new spiropyrrolidine derivatives were designed, synthesized, characterized and evaluated for their in vitro antimicrobial, antioxidant and antidiabetic potential. Antimicrobial results revealed that the designed compounds displayed good activity against clinical isolated strains, with 5d being the most potent (MIC 3.95 mM against Staphylococcus aureus ATCC 25923) compared to tetracycline (MIC 576.01 mM). The antioxidant activity was assessed by trapping DPPH, ABTS and FRAP assays. The results suggest remarkable antioxidant potential of all synthesized compounds, particularly 5c, exhibiting the strongest activity with IC₅₀ of 3.26 ± 0.32 mM (DPPH), 7.03 ± 0.07 mM (ABTS) and 3.69 ± 0.72 mM (FRAP). Tested for their α-amylase inhibitory effect, the examined analogues display a variable degree of α-amylase activity with IC₅₀ ranging between 0.55 ± 0.38 mM and 2.19 ± 0.23 mM compared to acarbose (IC₅₀ 1.19 ± 0.02 mM), with the most active compounds being 5d, followed by 5c and 5j, affording IC₅₀ of 0.55 ± 0.38 mM, 0.92 ± 0.10 mM, and 0.95 ± 0.14 mM, respectively. Preliminary structure-activity relationships revealed the importance of such substituents in enhancing the activity. Furthermore, the ADME screening test was applied to optimize the physicochemical properties and determine their drug-like characteristics. Binding interactions and stability between ligands and active residues of the investigated enzymes were confirmed through molecular docking and dynamic simulation study. These findings provided guidance for further developing leading new spiropyrrolidine scaffolds with improved dual antimicrobial and antidiabetic activities.

Keywords: ADME; antidiabetic; antimicrobial; antioxidant; molecular docking and dynamic simulation; spiropyrrolidine derivatives.

MeSH terms

Anti-Bacterial Agents / chemistry
Anti-Infective Agents* / pharmacology
Antioxidants* / chemistry
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology
Molecular Docking Simulation
Quinoxalines
Structure-Activity Relationship
alpha-Amylases / metabolism

Substances

Antioxidants
2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid
Quinoxalines
Hypoglycemic Agents
Anti-Bacterial Agents
Anti-Infective Agents
alpha-Amylases

Grants and funding

MDR-22 021./Scientific Research Deanship at University of Ha'il - Saudi Arabia