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

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.

Combined Experimental and Computational Study of V-Substituted Lindqvist Polyoxotungstate: Screening by Docking for Potential Antidiabetic Activity

“…Acarbose (ACB) works by slowing the digestion as well as absorption of carbohydrates in the intestine of the host, thereby reducing the postprandial rise in blood glucose levels. The literature has shown that acarbose possesses a notably potential benefit; however, it is reported that ACB is one of the major causes of gastrointestinal disturbance, which limits its level of consumption. , To this effect, the use of compound (1) was evaluated by docking the organic molecule against the 3wyl (α-glucosidase or diabetic receptor) biomolecule. The result obtained is compared with the standard drug (ACB) and reported in Table S5.…”

Chemistry, Synthesis, and Structure Activity Relationship of Anticancer Quinoxalines

“…MD simulation indicated that the ligands remained in the stable docked complex and that the molecules did not leave the VEGFR-2 active site during the 200 ns simulation. Figure 14 shows the molecular structure of the model 25 and the designed derivatives (26)(27)(28)(29)(30) while Table 3 shows the computed activities of these derivatives [101]. Table 3.…”

“…It is a low-melting solid (29-30 • C), soluble in water, and a weak base (pKa = 0.56) [15]. Several studies were performed and displayed a wide range of pharmacological activities for quinoxaline derivatives (Figure 1) [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Additionally, quinoxalines are used for crop protection as a component of insecticides, herbicides, and fungicides [31][32][33][34][35].…”

Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches

“…In this regard, isatin derivatives have gained the passion of many researchers owing to their broad spectrum of biological activities. For many years, our research team has focused on the identification of new biologically active biomolecules/small molecules with promising biological activities [ [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] ], mainly those α-amylase and α-glucosidase inhibitors [ [71] , [72] , [73] , [74] , [75] , [76] ]. In this context, our work has been devoted to the design and the synthesis of isoxazolidine-isatin hybrids for more potent, selective α-glucosidase and α-amylase inhibitors.…”