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.

Versatile anti-infective properties of pyrido- and dihydropyrido[2,3-d]pyrimidine-based compounds.

A series of 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine and 1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives was prepared and screened for antiparasitic and viral RNase H inhibitory activity. Several compounds showed considerable activity against Toxoplasma gondii parasites and Leishmania major amastigotes, which warrants further investigation. Based on the structural similarities of certain derivatives with common viral RNase H inhibitors, a HIV-1 RNase H assay was used to study the RNase H inhibition by selected test compounds. Docking of active derivatives into the active site of the HIV-1 RNase H enzyme was carried out. The new compound 2a, inactive in the antiparasitic tests, showed distinct HIV-1 RNase H inhibition. Thus, ring substitution determines antiparasitic or HIV-1 RNase H inhibitory activity of this promising compound class.

Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents.

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50 =4.5-5.8 µM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50 =2.0-3.5 µM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T. b. brucei cells.

Synthesis, characterization, anticancer activity and molecular docking of metal complexes bearing a new Schiff base ligand.

2-((E)-((4-(((E)-4-Nitrobenzylidene)amino)phenyl)imino)methyl)naphthalen-1-ol, was synthesised followed by metalation with Fe(III), Co(III), Cu(II), Zn(II) and Ni(II) metals. The compounds were characterised by different methods CHN, AAS, IR, NMR, XRD, TGA and UV-Vis. The results reveal that the ligand has bidentate behavior, and it is bound with metals by a coordination bond through both the nitrogen atom of the azomethine group and the oxygen atom, this provided an octahedral geometry. The X-ray diffraction of the compounds indicate that the ligands and complexes of Co(III), Fe(III) and Zn(II) have a crystalline nature, whereas the Ni(II) and Cu(II) have an amorphous structure. The agar diffusion method (hole plate) was used to evaluate the ligand's and its complexes' antibacterial and antifungal effects on Salmonella enterica serovar typhi and Candida albicans, respectively. It was observed that the Fe(III) complex had the best activity among the compounds against microbial strains. Cytotoxicity of new metal complexes was also assessed against A549, HepG-2 and PC-3 cancer cells. Results demonstrated that the Cu(II) complex displayed the preeminent activity among the synthesised compounds against all the tested cell lines. Furthermore, molecular docking simulation revealed that the Fe(III) complex is shown to have a high affinity with the active sites of two targets of microbial strains. Also, the Cu(II) complex shown to has a high affinity with the active sites of three targets of A-549, HepG-2 and PC-3 cancer cells, which was confirmed by the formation of the different modes of interaction.Communicated by Ramaswamy H. Sarma.

Molecular docking/dynamics simulations, MEP analysis, bioisosteric replacement and ADME/T prediction for identification of dual targets inhibitors of Parkinson's disease with novel scaffold.

Monoamine oxidase B and Adenosine A2A receptors are used as key targets for Parkinson's disease. Recently, hMAO-B and hA2AR Dual-targets inhibitory potential of a novel series of Phenylxanthine derivatives has been established in experimental findings. Hence, the current study examines the interactions between 38 compounds of this series with hMAO-B and hA2AR targets using different molecular modeling techniques to investigate the binding mode and stability of the formed complexes. A molecular docking study revealed that the compounds L24 ((E)-3-(3-Chlorophenyl)-N-(4-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) phenyl) acrylamide and L32 ((E)-3-(3-Chlorophenyl)-N-(3-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)acrylamide) had a high affinity (S-score: -10.160 and -7.344 kcal/mol) with the pocket of hMAO-B and hA2AR targets respectively, and the stability of the studied complexes was confirmed during MD simulations. Also, the MEP maps of compounds 24 and 32 were used to identify the nucleophilic and electrophilic attack regions. Moreover, the bioisosteric replacement approach was successfully applied to design two new analogs of each compound with similar biological activities and low energy scores. Furthermore, ADME-T and Drug-likeness results revealed the promising pharmacokinetic properties and oral bioavailability of these compounds. Thus, compounds L24, L32, and their analogs can undergo further analysis and optimization in order to design new lead compounds with higher efficacy toward Parkinson's disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00139-3.

Investigation of [3H]diazepam derivatives as allosteric modulators of GABAA receptor α1ß2γ2 subtypes: combination of molecular docking/dynamic simulations, pharmacokinetics/drug-likeness prediction, and QSAR analysis.

In this paper, a data set of [3H] diazepam derivatives was analyzed using various computational methods: molecular docking/dynamic simulations, and QSAR analysis. The main aims of these studies are to understand the binding mechanisms by which benzodiazepines allosterically modulate GABAA receptor α1ß2γ2 subtypes, from inducing neuronal inhibition at lower doses to the anesthetic effect at higher doses, and also, to define the structural requirements that contribute to improving the response of GABAA/α1ß2γ2 receptor to benzodiazepine drugs. The results of the molecular docking study allowed selecting Ro12-6377 and proflazepam as the best modulators for the four binding sites simultaneously. Subsequently, the stability of the selected complexes was investigated by performing molecular dynamics simulation. The latter confirmed the features of both modulators to exert direct effects on the chloride-channel lining residues. Pharmacokinetics and drug-likeness profile were assessed through in silico tool. Furthermore, a QSAR analysis was conducted using an improved vemolecular dynamics simulations proposed byrsion of PLS regression. The goodness of fit and the predictive power of the resulting PLS model were estimated according to internal and external validation parameters: R2 = 0.632, R2adj = 0.584, F = 12.806; p-value = 6.2050e - 07, Q2loo = 0.639, and Q2F3 = 0.813. Clearly, the obtained results ensure the predictive ability of the developed QSAR model for the design of new high-potency benzodiazepine drugs. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02029-4.

Efficient Synthesis of 2-Aminopyridine Derivatives: Antibacterial Activity Assessment and Molecular Docking Studies.

A new and suitable multicomponent one-pot reaction was developed for the synthesis of 2-amino-3-cyanopyridine derivatives. BACKGROUND: This synthesis was demonstrated by the efficient and easy access to a variety of substituted 2-aminopyridines using enaminones as key precursors under solvent-free conditions. METHODS: A range of spectroscopic techniques was used to determine and confirm the chemical structures (FTIR, 1H NMR, 13C NMR). The antimicrobial potency of synthesized compounds (2a-d) was tested using disk diffusion assays, and the Minimum Inhibitory Concentration (MIC) for the active compounds was determined against a panel of microorganisms, including Gram-positive and Gram-negative bacteria and yeasts. Moreover, a docking analysis was conducted by Molecular Operating Environment (MOE) software to provide supplementary information about the potential, as well as an ADME-T prediction to describe the pharmacokinetic properties of the best compound and its toxicity. RESULTS: The results of the antimicrobial activity indicated that compound 2c showed the highest activity against Gram-positive bacteria, particularly S. aureus and B. subtilis whose MIC values were 0.039 ± 0.000 µg·mL-1. The results of the theoretical study of compound 2c were in line with the experimental data and exhibited excellent antibacterial potential. CONCLUSIONS: On the basis of the obtained results, compound 2c can be used as an antibacterial agent model with high antibacterial potency.

In silico design of enzyme α-amylase and α-glucosidase inhibitors using molecular docking, molecular dynamic, conceptual DFT investigation and pharmacophore modelling.

Type 2 diabetes mellitus (T2DM) is characterized by elevated blood glucose levels and can lead to serious complications such as nephropathy, neuropathy, retinopathy and cardiovascular disease. The aim of this work is to identify and investigate the inhibition mechanism of natural flavonoids and phenolics acids against, the α-amylase (αA) and α-glucosidase (αG). Therefore, we used different approaches; such as conceptual DFT and pharmacophore mapping in addition to molecular mechanics, dynamics and docking simulations. Whereas, a close agreement was found out to decide that Linarin (Flavones) provides more optimized inhibition of αA and αG enzymes. Our results have shown that Linarin could be useful as preventative agent, and possibly therapeutic modality for the treatment of metabolic diseases.Communicated by Ramaswamy H. Sarma.

Potential inhibitors of angiotensin converting enzyme 2 receptor of COVID-19 by Corchorus olitorius Linn using docking, molecular dynamics, conceptual DFT investigation and pharmacophore mapping.

A novel coronavirus, previously designated 2019-nCoV, was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China, at the end of 2019. Our objective focuses on the in silico study to screen for an alternative drug that can block the activity of the angiotensin converting enzyme 2 (ACE2), which is a key protein in the physiology of Covid-19, necessary for the entry of the SARS-Cov-2 virus into the host's cells using natural compounds especially phenolic antioxidants, polyphenolics and pharmaceutically phytochemicals derived from the leaves of Corchorus olitorius Linn, appear to be very potential in controlling virus-induced infection. The results of the docking simulation revealed that méthyl-1,4,5-tri-O-caféoyl quinate has a stronger bond, high affinity and gives the best docking scores compared to, the co-crystallized inhibitor (PRD_002214) of the enzyme ACE2, chloroquine, hydroxychloroquine, captopril and simerprevir antiviral drugs. The ADMET properties, Pharmacokinetics and Medicinal Chemistry & P450 site of metabolism prediction, pharmacophore Mapper enzyme revealed that the compound méthyl-1,4,5-tri-O-caféoyl quinate generates a hypothesis which can be applied successfully in biological screening for further experiments. The novel MD computational technique study showed better conformational movements result for the méthyl-1,4,5-tri-O-caféoyl quinate-ACE2 docked complex. Therefore méthyl-1,4,5-tri-O-caféoyl quinate may be considered to be potential inhibitor of the main protease enzyme of virus, but need to be investigated in vivo and in vitro for further drug development process.Communicated by Ramaswamy H. Sarma.

Discovery of potential SARS-CoV 3CL protease inhibitors from approved antiviral drugs using: virtual screening, molecular docking, pharmacophore mapping evaluation and dynamics simulation.

The spread of corona-virus disease 2019 (COVID-19) has been faster than any other corona-viruses that have succeeded in crossing the animal-human barrier. This disease, caused by the severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2/2019-nCoV) posing a serious threat to global public health and local economies. There are three responsible for this disease; SARS-CoV-2, SARS-CoV and MERS-CoV. Whereas our goal is to test the affinity for a new class of compounds obtained from a hybridization of Chloroquine, Amodiaquine and Mefloquine with three targets SARS-CoV-2, SARS-CoV and MERS-CoV, in order to find new compounds as new inhibitors against Covid-19. In this work, we first used: the molecular docking/dynamics methods and ADME properties to study interaction and affinity between eight new compounds against three targets involved in the Covid-19. The results of the docking simulations and dynamics revealed that inhibitor of the malaria (Ligand 87) has an affinity to interact with SARS-CoV-2, SARS-CoV and MERS-CoV targets and they can be good inhibitors for treatment of Covid-19. Moreover, they give best affinity compared to the Remdesivir and Chloroquine and other clinical tests. The Pharmacokinetics was justified by means of lipophilicity and high coefficient of skin permeability. The in silico evaluation of ADME and drug-likeness revealed that L87 has higher absorption in the intestines with good bioavailability. However, an additional in vitro and/or in vivo experimental study should make it possible to verify the theoretical results obtained in silico.Communicated by Ramaswamy H. Sarma.

An integrated in silico and in vivo approach to determine the effects of three commonly used surfactants sodium dodecyl sulphate, cetylpyridinium chloride and sodium laureth sulphate on growth rate and hematology in Cyprinus carpio L.

The purpose of this work is to evaluate the homology modeling, in silico prediction, and characterization of somatotropin and erythropoietin from Cyprinus carpio as well as molecular docking and simulation experiments between the modeled proteins and surfactants sodium dodecyl sulfate (SDS), sodium laureth sulfate (SLES) and cetylpyridinium chloride (CPC). Using the best fit template structure, homology modeling of somatotropin and erythropoietin of Cyprinus carpio respectively was conducted. The model structures were improved further with 3Drefine, and the final 3D structures were verified with PROCHEK, ERRATA and ProQ. The physiochemical, as well as the stereochemical parameters of the modeled proteins, were evaluated using ExPASy's ProtParam. Molecular docking calculations, protein-ligand interactions, and protein flexibility analysis were carried out to determine the binding pattern of each ligand to the targeted proteins and their effect on the overall proteins' conformation. Our in silico analysis showed that hydrophobic interactions with the active site amino acid residues of the modeled proteins (somatotropin and erythropoietin) were more prevalent than hydrogen bonds and salt bridges that affect the flexibility and stability of the somatotropin and erythropoietin as revealed from our protein flexibility analysis. The in vivo analysis showed that sublethal concentrations of SDS, SLES, and CPC negatively affected the growth and hematological parameters of Cyprinus carpio. Hence, it may be inferred from the study that the alterations in the flexibility of somatotropin and erythropoietin of Cyprinus carpio upon addition of SDS, CPC and SLES might be attributable to the reduction in growth and hematological parameters.

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.

In silico evaluation of phenolic compounds as inhibitors of Α-amylase and Α-glucosidase.

The aim of the present study focuses on the molecular docking approach to screen alternative drug that can regulate the hyperglycemia by down-regulating α-glucosidase and α-amylase activity using phenolic compounds: tannic acid (L1), catechin (L2), gallic acid (L3), quercetin (L5) and epicatechin (L6). L1 gives the best docking scores, its interaction with α-amylase and α-glucosidase has the lowest energy score compared to the other complexes and to the acarbose (L4). L1 forms strong five H-donor interactions with residues of active site of α-amylase and three H-donor interactions with α-glucosidase. The in silico evaluation of the unfavorable absorption, distribution, metabolism, and elimination (ADME) properties and drug-likeness revealed that L5 has high absorption compared to tannic acid and to the other compounds. This study revealed for the first time that tannic acid is a functional inhibitor of α-glucosidase and α-amylase activities and can be used as alternative for the regulation of post-prandial hyperglycaemia. Communicated by Ramaswamy Sarma.

Combined QSAR, molecular docking and molecular dynamics study on new Acetylcholinesterase and Butyrylcholinesterase inhibitors.

BACKGROUND AND PURPOSE: This work deals with several molecular modeling methods used to discover new therapeutic agents for treating the Alzheimer's disease (AD). The cholinergic hypothesis was initially presented over 30 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain. Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are of the keys targets of drugs for treating AD. METHODS: QSAR, Molecular Docking/Dynamics and ADME properties were carried out in order to study 36 compounds that belong to the 4-[(diethylamino)methyl]-phenol derivatives and test their AChE and BuChE inhibitory activities, MOE, HyperChem and others softwares were used to find the best compounds with high affinity. RESULTS: The QSAR models exhibited good statistical values for both targets AChE (R2adj = 0.660, q2 = 0.70, F-ratio = 18.008) and BuChE (R2adj = 0.726, q2 = 0.75, F-ratio = 31.864). The interactions between the studied inhibitors and our targets were further explored through molecular docking and molecular dynamics simulations. A few key residues (TRP279, TYR334, PHE330 and TRP84) at the binding site of AChE and key residues (HIS438, TYR332, PHE329 and TRP82) at the binding site of BuChE were identified. CONCLUSION: Based on this study compounds 23 and 28 have no violated Lipinski's rule of five and thus, showing the possibility of being potential candidates for further studies in drug development process against the AChE and BuChE targets respectively.

Production and mechanical properties of Ti-5Al-2.5Fe-xCu alloys for biomedical applications.

In this study, the mechanical, antibacterial properties and cell toxicity response of Ti-5Al2.5Fe alloy with different copper contents were investigated. The alloys were prepared by high-energy ball milling using elemental Ti, Al, Fe, and Cu powders and consolidated by a uniaxial vacuum hot press. Staphylococcus aureus strain ATCC 29213 and Escherichia coli strain ATCC 25922 were used to determine the antibacterial properties of the sintered alloys. The in vitro cytotoxicity of the samples was evaluated with HeLa (ATTC, CCL-2) cells using thiazolyl blue tetrazolium bromide. The mechanical behavior of the samples was determined as a function of hardness and bending tests and analyzed by scanning electron microscopy, energy dispersive x-ray spectroscopy, optical microscopy and x-ray diffraction (XRD). The results showed that the Cu content significantly improved the antibacterial properties. Cu addition prevented the formation of E. coli and S. aureus colonies on the surface of the samples. All samples exhibited very good cell biocompatibility. The alloys with different copper contents showed different mechanical properties, and the results were correlated by microstructural and XRD analyses in detail. Our results showed that Cu has a great effect on the Ti5Al2.5Fe alloy and the alloy is suitable for biomedical applications with enhanced antibacterial activity.