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
Affiliations
Nouha Bouali
Department of Biology, College of Science, Hail University, P.O. Box 2440, Hail 2440, Saudi Arabia
Manel Ben Hammouda
Laboratory of Heterocyclic Chemistry Natural Product and Reactivity/CHPNR, Department of Chemistry, Faculty of Science of Monastir, University of Monastir, Monastir 5000, Tunisia
Iqrar Ahmad
Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India
Siwar Ghannay
Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia
Amira Thouri
Laboratory of Bioresources, Biology Integrative and Valorization, Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir 5000, Tunisia
Amal Dbeibia
Laboratory of Analyzes, Treatment and Valorization of Environmental Pollutants and Products, Faculty of Pharmacy of Monastir, University of Monastir, Monastir 5019, Tunisia
Harun Patel
Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India
Walid Sabri Hamadou
Department of Biology, College of Science, Hail University, P.O. Box 2440, Hail 2440, Saudi Arabia
Karim Hosni
Laboratoire des Substances Naturelles, Institute National de Recherche et d’Analyse Physico-Chimique, Biotechpôle de Sidi Thabet, Sidi Thabet 2020, Tunisia
Mejdi Snoussi
Department of Biology, College of Science, Hail University, P.O. Box 2440, Hail 2440, Saudi Arabia
Mohd Adnan
Department of Biology, College of Science, Hail University, P.O. Box 2440, Hail 2440, Saudi Arabia
Md Imtaiyaz Hassan
Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
Emira Noumi
Department of Biology, College of Science, Hail University, P.O. Box 2440, Hail 2440, Saudi Arabia
Kaïss Aouadi
Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia
Adel Kadri
Department of Chemistry, Faculty of Science and Arts of Baljurashi, Albaha University, Al Bahah P.O. Box 1988, Saudi Arabia
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.
