Synthesis of Tetracyclic Spirooxindolepyrrolidine-Engrafted Hydantoin Scaffolds: Crystallographic Analysis, Molecular Docking Studies and Evaluation of Their Antimicrobial, Anti-Inflammatory and Analgesic Activities.

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out.

Design of Novel Enantiopure Dispirooxindolopyrrolidine-Piperidones as Promising Candidates toward COVID-19: Asymmetric Synthesis, Crystal Structure and In Silico Studies.

Despite the effectiveness of COVID-19 vaccines, there is still an urgent need for discovering new anti-viral drugs to address the awful spread and transmission of the rapidly modifiable virus. In this study, the ability of a small library of enantiomerically pure spirooxindolopyrrolidine-grafted piperidones to inhibit the main protease of SARS-CoV-2 (Mpro) is evaluated. These spiroheterocycles were synthesized by 1,3-dipolar cycloaddition of various stabilized azomethine ylides with chiral dipolarophiles derived from N-[(S)-(-)-methylbenzyl]-4-piperidone. The absolute configuration of contiguous carbons was confirmed by a single crystal X-ray diffraction analysis. The binding of these compounds to SARS-CoV-2 Mpro was investigated using molecular docking and molecular dynamics simulation. Three compounds 4a, 4b and 4e exhibited stable binding modes interacting with the key subsites of the substrate-binding pocket of SARS-CoV-2 Mpro. The synthesized compounds represent potential leads for the development of novel inhibitors of SARS-CoV-2 main protease protein for COVID-19 treatment.

Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds.

A novel series of 14 spiropyrrolidines bearing thiochroman-4-one/chroman-4-one, and oxindole/acenaphthylene-1,2-dione moieties were synthesized and characterized by spectroscopic techniques, as well as by three X-ray diffraction studies, corroborating the stereochemistry. Quantum chemical calculations studies, using the DFT approach, were performed to rationalize the stereochemical outcome. These N-heterocycles were evaluated for their antibacterial and antifungal activities against some pathogenic organisms. Several compounds displayed moderate to excellent activity towards the screened microbe strains in the study compared to Amoxicillin (AMX), Ampicillin (AMP), and Amphotericin B. Furthermore, a structural activity relationship (SAR) was established considering the synthesized compounds. Pharmacokinetic studies reveal that these derivatives exhibit an acceptable predictive ADMET profile (Absorption, Distribution, Metabolism, Excretion and Toxicity) and good drug-likeness.

Diversity-Oriented Synthesis of Spiropyrrolo[1,2-a]isoquinoline Derivatives via Diastereoselective and Regiodivergent Three-Component 1,3-Dipolar Cycloaddition Reactions: In Vitro and in Vivo Evaluation of the Antidiabetic Activity of Rhodanine Analogues.

An efficient diastereoselective route is developed to get access to novel spiropyrrolo[1,2-a]isoquinoline-oxindole skeletons by a one-pot three-component [3 + 2] cycloaddition reaction of (Z)-5-arylidene-1,3-thiazolidine-2,4-diones, isatin derivatives, and 1,2,3,4-tetrahydroisoquinoline (THIQ). Interestingly, the regioselectivity of the reaction is both temperature- and solvent-dependent, allowing the synthesis of two regioisomeric endo-dispiropyrrolo[2,1-a]isoquinolineoxindoles in excellent yield. Unprecedentedly, each isomeric dispiropyrrolo[2,1-a]isoquinolineoxindole endured retro-1,3-dipolar cycloaddition/recycloaddition reactions under thermal or catalytic conditions to regenerate the corresponding regioisomeric counterpart. In addition, DFT calculations were performed at the M062X/6-31++g(d,p) level of theory to unravel the origin of the reversal of regioselectivity and endo-stereoselectivity of the title 1,3-dipolar cycloaddition reactions. Upon treatment of Isatin, THIQ with (Z)-4-arylidene-5-thioxo-thiazolidin-2-ones as dipolarophiles, unusual rhodanine analogues were formed, along with smaller amounts of a dispirooxindole-piperazine. The structure and the relative configuration of these N-heterocycles were unambiguously assigned by spectroscopic techniques and confirmed by four single-crystal structures. In vitro and in vivo studies reveal that the novel rhodanine derivatives exert antidiabetic activity. The binding affinity with the active site of the enzyme α-amylase was studied by molecular docking. Furthermore, the bioavailability assessed through virtual ADME parameters (Absorption, Distribution, Metabolism, Elimination pharmacokinetics) and the excellent fit with the Lipinski and Veber rules predict good drug-likeness properties for a bromo-substituted 2-sulfanylidene-1,3-thiazolidin-4-one.

Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel α-amylase inhibitors.

In a sustained search for novel α-amylase inhibitors for the treatment of type 2 diabetes mellitus (T2DM), we report herein the synthesis of a series of nineteen novel rhodanine-fused spiro[pyrrolidine-2,3'-oxindoles]. They were obtained by one-pot three component [3 + 2] cycloaddition of stabilized azomethine ylides, generated in situ by condensation of glycine methyl ester and the cyclic ketones 1H-indole-2,3-dione (isatin), with (Z)-5-arylidine-2-thioxothiazolidin-4-ones. The highlight of this protocol is the efficient high-yield construction of structurally diverse rhodanine-fused spiro[pyrrolidine-2,3'-oxindoles] scaffolds, including four contiguous stereocenters, along with excellent regio- and diastereoselectivities. The stereochemistry of all compounds was confirmed by NMR and corroborated by an X-ray diffraction study performed on one derivative. All cycloadducts were evaluated in vitro for their α-amylase inhibitory activity and showed good α-amylase inhibition with IC50 values ranging between 1.49 ± 0.10 and 3.06 ± 0.17 µM, with respect to the control drug acarbose (IC50 = 1.56 µM). Structural activity relationships (SARs) were also established for all synthesized compounds and the binding interactions of the most active spiropyrrolidine derivatives were modelledby means of molecular insilico docking studies. The most potent compounds 5 g, 5 k, 5 s and 5 l were further screened in vivo for their hypoglycemic activity in alloxan-induced diabetic rats, showing a reduction of the blood glucose level. Therefore, these spiropyrrolidine derivatives may be considered as promising candidates for the development of new classes of antidiabetic drugs.

Antiobesity and antidiabetes effects of Cyperus rotundus rhizomes presenting protein tyrosine phosphatase, dipeptidyl peptidase 4, metabolic enzymes, stress oxidant and inflammation inhibitory potential.

Diabetes is a significant global health concern that increases the vulnerability to various chronic illnesses. In view of this issue, the current research aimed to examine the effects of administering an extract derived from the tubers of Cyperus rotundus L (CrE) on obesity, type 1 diabetes, and liver-kidney toxicity. Through the utilization of HPLC-DAD analysis, it was discovered that the extract contained several components, including quercetin (47.8%), luteolin glucoside (17%), luteolin (7.56%), apigenin-7-glucoside (6.29%), naringinin (4.52%), and seven others. In vitro experiments they have demonstrated that CrE effectively inhibited key digestive enzymes associated with obesity and type 2 diabetes, such as DPP-4, PTP1B, lipase, and α-amylase, as evidenced by their respective IC50 values are about 23, 51,83, and 67 µg/ml respectively. Furthermore, when diabetic rats were administered CrE, the activity of pancreatic enzymes linked to inflammation, namely 5-lipoxygenase (5-LO), hyaluronidase (HAase), and myeloperoxidase (MPO), was significantly suppressed by 48, 41, 75, and 47%, respectively. Moreover, CrE exhibited protective effects on pancreatic ß-cells by inhibiting the formation of thiobarbituric acid reactive substances (TBARS) by 65% and the induction of superoxide Dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities by 62, 108, and 112% respectively as compared to diabetic untreated rat. Additionally, CrE significantly inhibited the activities of intestinal, pancreatic, and serum lipase and α-amylase activities. In diabetic rats, CrE administration suppressed glycogen phosphorylase (GP) stimulated glycogen synthase (GS) activities by 45 and 30%; and this increased liver glycogen content by 45%. Furthermore, CrE modulated key hepatic enzymes involved in carbohydrate metabolism, including hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase (G6P), and fructose-1,6-bisphosphatase (FBP). Notably, the average food and water intake (AFI and AWI) of diabetic rats treated with CrE was reduced by 15 and 16% respectively as compared to those without any treatment. Therefore, this study demonstrated the effectiveness of Cyperus rotundus tubers in preventing and treating obesity and diabetes.