Design, synthesis, and molecular modeling of heterodimer and inhibitors of α-amylase as hypoglycemic agents.

A series of rosiglitazone-based heterodimers were designed and synthesized, and their α-amylase and antioxidant activity was evaluated. The binding mode of the compounds at the active site of PPARγ and α-amylase enzyme was explored using MolDock docking method. In molecular docking studies against crystal structure of PPARγ (PDB code: 1FM6), compounds 10 and 13 showed interaction with amino acids Arg379, Asp379, Asn385, Ala387, Glu388, Val389, Glu390, and Lys438. Docking results of α-amylase enzyme (PDB code: 5EOF) with compounds 10 and 13 showed excellent interaction with amino acids Ala169, Lys172, Asp173, Tyr174, Val175, Arg176, and Lys178. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. All synthesized compounds were subjected to in vitro α-amylase activity and antioxidant activity. Compounds 10 and 13 were to possess higher potency than acarbose, and most of the compounds showed antioxidant activity. Additionally, the most active compound 10 was evaluated for in vivo anti-diabetic activity.

Phytochemical analysis, in silico study and toxicity profile of Cycas pectinata Buch.-Ham seed in mice.

Fruit of Cycas pectinata Buch.-Ham has been used as medicine by the local community in some parts of the north eastern state of India. Despite its uses for different purposes, the safety assessment study has not been conducted. Therefore, we have evaluated the acute and the sub-acute toxicity of methanolic extract of C. pectinata fruit (CPFE) in a mice model via oral route of administration. Phytochemicals analysis was carried out by liquid chromatography-mass spectroscopy (LC-MS), nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FTIR). The acute toxicity study was performed at a single dose of 1000, 3000 and 5000 mg/kg and the sub-acute toxicity study at a dose of 100, 300 and 500 mg/kg was administered daily for 28 days. The calculated Lethal dose 50 (LD50) of CPFE was found to be 4000 mg/kg. Both acute and sub-acute studies showed that 5000 mg/kg and 500 mg/kg dose was toxic to the mice. The results of acute toxicity showed CPFE could have a mild toxic effect on the kidney at a dose of 3000 and 5000 mg/kg, as some deteriorated changes in the kidney along with increase creatinine levels were observed. Acute toxicity also showed an increase in white blood cells (WBC) at a dose of 3000 mg/kg.However, sub-acute toxicity studies do not show any detrimental effects on liver, kidney and hematological parameters. Thus, it can be suggested that CPFE at a dose of 100 and 300 mg/kg would be safe for consumption. The phytochemicals analysis by LC-MS, NMR and FTIR showed the presence of 32 major chemical compounds with certain biological activity like anti-neoplastic, antioxidant, and possible modulator of steroid metabolism (cholesterol antagonist and agonist of testosterone 17ß-dehydrogenase) as predicted by PASS analysis.

Potential drug development and therapeutic approaches for clinical intervention in COVID-19.

While the vaccination is now available to many countries and will slowly dissipate to others, effective therapeutics for COVID-19 is still illusive. The SARS-CoV-2 pandemic has posed an unprecedented challenge to researchers, scientists, and clinicians and affected the wellbeing of millions of people worldwide. Since the beginning of the pandemic, a multitude of existing anti-viral, antibiotic, antimalarial, and anticancer drugs have been tested, and some have shown potency in the treatment and management of COVID-19, albeit others failed to leave any positive impact and a few also became controversial as they showed mixed clinical outcomes. In the present article, we have brought together some of the candidate therapeutic drugs being repurposed or used in the clinical trials and discussed their clinical efficacy and safety for COVID-19.

Step toward repurposing drug discovery for COVID-19 therapeutics through in silico approach.

The outbreak of SARS-CoV-2 has become a threat to global health and has led to a global economic crisis. Although the researchers worldwide are putting tremendous effort toward gaining more insights into this zoonotic virus and developing vaccines and therapeutic drugs, no vaccine or drug is yet available to combat COVID-19 effectively. Drug discovery is often a laborious, time-consuming, and expensive task. In this time of crisis, employing computational methods could provide a feasible alternative approach that can potentially be used for drug discovery. Therefore, a library of several antiparasitic and anti-inflammatory drugs was virtually screened against SARS-CoV-2 proteases to identify potential inhibitors. The identified inhibitory drugs were further analyzed to confirm their activities against SARS-CoV-2. Our results could prove to be helpful in repurposing the drug discovery approach, which could substantially reduce the expenses, time, and resources required.

Anti-diabetic drugs recent approaches and advancements.

Diabetes is one of the major diseases worldwide and is the third leading cause of death in the United States. Anti-diabetic drugs are used in the treatment of diabetes mellitus to control glucose levels in the blood. Most of the drugs are administered orally, except for a few of them, such as insulin, exenatide, and pramlintide. In this review, we are going to discuss seven major types of anti-diabetic drugs: Peroxisome proliferator-activated receptor (PPAR) agonist, protein tyrosine phosphatase 1B (PTP1B) inhibitors, aldose reductase inhibitors, α-glucosidase inhibitors, dipeptidyl peptidase IV (DPP-4) inhibitors, G protein-coupled receptor (GPCR) agonists and sodium-glucose co-transporter (SGLT) inhibitors. Here, we are also discussing some of the recently reported anti-diabetic agents with its multi-target pharmacological actions. This review summarises recent approaches and advancement in anti-diabetes treatment concerning characteristics, structure-activity relationships, functional mechanisms, expression regulation, and applications in medicine.

Synthesis, biological evaluation and molecular modeling study of pyrazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents.

A novel series of pyrazole derivatives were synthesized and evaluated in vivo for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Among all compounds, 5a, and 5b showed comparable anti-inflammatory activity to Nimesulide, the standard drug taken for the studies. In silico (docking) studies were carried out to investigate the theoretical binding mode of the compounds to target the cyclooxygenase (COX-2) using Autodock 4.2.

Molecular docking study of conformational polymorph: building block of crystal chemistry.

Two conformational polymorphs of novel 2-[2-(3-cyano-4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-ethoxy]-4,6-dimethyl nicotinonitrile have been developed. The crystal structure of both polymorphs (1a and 1b) seems to be stabilized by weak interactions. A difference was observed in the packing of both polymorphs. Polymorph 1b has a better binding affinity with the cyclooxygenase (COX-2) receptor than the standard (Nimesulide).

Non-Covalent Interactions in the Self-Assembly of Dihydropyridone Supramolecules and In Vitro Anti-Cancer Assessment in Human Lung Adenocarcinoma Cell Line (A549).

The synthesis of dihydropyridone derivatives has been reported by ring rearrangement of pyrans using iodine and formic acid as a catalyst separately. Dihydropyridones were crystallized subjected for single-crystal X-ray crystallography to acquire their structural parameters. The different non-covalent interactions involved within the supramolecular systems were studied and validated using Hirshfeld surface plot analysis. N-H⋅⋅⋅O interactions between the lactam group dominate. Still, other non-covalent interactions such as C-H⋅⋅⋅N, C-H⋅⋅⋅O, C-H⋅⋅⋅C, N-H⋅⋅⋅N, C-H⋅⋅⋅π, and lone pair⋅⋅⋅π systems act as the driving force in facilitating the self-assembly of the dihydropyridone supramolecules. The synthesized compounds were analyzed by in vitro techniques using human lung adenocarcinoma (A549) to evaluate their cytotoxic activities. Ethyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-oxo-1,4,5,6- tetrahydropyridine-3-carboxylate has shown the highest cytotoxicity among all the synthesized compounds. Molecular recognition properties of the dihydropyridone compounds were also studied, employing molecular docking tools to gain insight into the binding mode inside the allosteric binding pocket of the Eg5 protein through non-covalent interactions.

Synthesis of a Pyridone-Based Phthalimide Fleximer and Its Characterization and Supramolecular Property Evaluation.

In this study, a novel pyridone-based phthalimide fleximer, that is, ethyl 5-cyano-6-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-4-(3-methoxyphenyl)-2-methylnicotinate, was synthesized, and its structure was established by the single-crystal X-ray diffraction method. The supramolecular self-assembly of the titled compound through noncovalent interactions was then investigated thoroughly. The titled compound crystallized with two symmetry-independent molecules (A and B, Z' = 2). In agreement with experimental observations, our density functional theory calculations also showed that the titled compound has a flexible motif and can occur in various conformations, including molecules A and B. The investigation of the supramolecular framework revealed that the molecules are notably bound by the nonclassical C-H···O and C-H···N hydrogen bonds and C-H···π interactions. Hirshfeld surface analysis was carried out to quantify the various intermolecular interactions. The dual anti-inflammatory activity of the tilted compound was also explored by molecular docking in the active sites of 5-LOX and COX-2 receptors, which revealed good binding affinities of -9.0 and -8.6 kcal/mol, respectively.

Green synthesis, structural analysis and anticancer activity of dihydropyrimidinone derivatives.

In this study, for the first time, we have used Citrus macroptera juice to synthesize dihydropyrimidine (DHPM) derivatives via the Biginelli reaction, which showed better yield, shorter reaction time, and did not require an organic solvent for the reaction. A series of DHPM derivatives were synthesized, and characterized, and structural analysis was achieved through SCXRD & Hirshfeld surface analysis. We observed that these synthesized dihydropyrimidine (DHPM) derivatives showed C-H⋯π, C-H⋯O, C-H⋯N, C-H⋯C, lone pair⋯π, π⋯π, etc. interactions. We also performed in silico studies for their inhibitory activities against human kinesin Eg5 enzyme, and the cytotoxic activity of the synthesized compounds was carried out against A549 lung adenocarcinoma cells. In silico analysis demonstrated that compounds with a chloro-group at the 3- or 4-position in the substituted ring of DHPM showed higher binding affinity for the human kinesin Eg5 enzyme (-7.9 kcal mol-1) than the standard drug monastrol (-7.8 kcal mol-1). Furthermore, in vitro cellular studies revealed that compounds with a chloro-group at the 3- or 4-position in the substituted ring of DHPM induced significant cell death in human A549 lung adenocarcinoma cells. This result indicates that a deactivating group (chlorine) at the 3- or 4-position in the substituted ring of DHPM might be a promising anticancer drug candidate for treating different types of cancers, particularly cancer of the lung.

Very strongly ferromagnetically coupled diradicals from mixed radical centers. II. Nitronyl nitroxide coupled to tetrathiafulvalene via spacers.

We predict large and positive intramolecular magnetic exchange coupling constants (J) for coupled diradicals constructed from nitronyl nitroxide and tetrathiafulvalene monoradical moieties. These diradicals have the general formula TTF-coupler-NN, where the couplers are mostly aromatic systems. Unrestricted density functional methodology (UB3LYP) has been used to optimize the molecular geometries of the triplet diradicals using the 6-311 g(d,p) basis set. This has been followed by single-point UB3LYP calculations for triplet and broken symmetry (BS) states using 6-311++g(3df,3pd) basis and the optimized triplet geometries. We find that the species comprising of ethylene (geminal coupling) and pyridine as couplers have singlet ground states whereas the other species have triplet ground states. These findings are in support of the spin alternation rule. The largest J value we predict is 648.6 cm(-1) for the molecule with the spacer pyrrole. We also determine the percent weightings of triplet and singlet components in the BS state, estimate the diradical nature, and calculate the relative weights of different singlet and triplet component functions in the BS solution in each case.

Novel anti-inflammatory agents based on pyrazole based dimeric compounds; design, synthesis, docking and in vivo activity.

Series of pyrazole ester prodrugs analogues have been synthesized and found to contain highly potent inhibitors of the cyclooxygenase-2 (COX-2) enzyme. The paper describes synthesis of the target pyrazole analogues. The structure of the synthesized mutual ester prodrugs (6-8c) were confirmed by (1)H-, (13)C-NMR mass spectroscopy (MS) and their purity were ascertained by TLC and elemental analyses. The biological in vivo evaluation of these compounds in experimental models (carrageenan-induced oedema) proved the presence of anti-inflammatory activity. Docking studies into the catalytic site of COX-2 were used to identify potential anti-inflammatory lead compounds. One lead derivative was chosen endowed with good binding energies.

A comprehensive insight on the recent development of Cyclic Dependent Kinase inhibitors as anticancer agents.

Cancer is one of the major leading causes of death worldwide despite many breakthroughs in the development of novel anticancer drugs. The heterodimer CDK-Cyclin complex plays an essential role in regulating cellular processes. For example, epigenetics, neuronal activity, gene transcription, metabolism, DNA repair, angiogenesis, and hematopoiesis. Consequently, CDKs are often deregulated and over-expressed, causing an uncontrolled proliferation in tumors. Due to their active role in cell cycle regulation and transcription activity, CDKs are conceived as promising targets to overcome cell proliferation. Therefore, designing and developing efficient Cyclic Dependent Kinase inhibitors is progressively becoming a credible solution in treating cancers. This review article emphasized the recent developments of cyclic dependent Kinase inhibitors with insights into their structure-activity relationship, molecular docking, and mechanism of action.

Base-mediated regio- and stereoselective intermolecular addition of alkynes to N-heterocycles.

The regio- and stereoselective addition of N-heterocycles to alkynes using KOH is reported. Formation of (Z)-isomers and their conversion to (E)-products were found to be dependent upon time as well as the choice of base. Selective attack of N-heterocycles on a more electrophilic alkynyl carbon was supported by DFT calculations, and the stereochemistry of the products was established by X-ray crystallographic studies and intramolecular cyclization of ortho-haloalkynes in indolo-[2,1-a]isoquinolines.

Importance of weak interactions in developing 1,3-bis(4,6-dimethyl-1H-nicotinonitrile-1-yl)1,3-dioxy propane polymorphs.

The structure of 1,3-bis(4,6-dimethyl-1H-nicotinonitrile-1-yl)1,3-dioxy propane polymorphs has been characterized by X-ray diffraction, FT-IR, 1H and 13C NMR spectroscopies. The influence of intra and intermolecular weak interactions is thoroughly studied in solid state using single crystal X-ray diffraction and FT-IR. These polymorphs belong to monoclinic space group 'P2(1/n)' and 'P2(1/c)'. These polymorphs have C-H⋯n (lone pair), hydrogen bonds, C-N⋯π, C-H⋯π and π⋯π intermolecular non-covalent interactions. These polymorphs are the result of weak interactions and solvent used in crystallization. The FT-IR spectra have been recorded in the solid phase and NMR has been recorded in solvent. The optimized geometry has been calculated by B3LYP methods using different basis sets. The FT-IR and NMR spectra of 1st polymorphs has been calculated at B3LYP/6-31G (d) level. The scaled theoretical wave number showed good agreement with the experimental values. These two polymorphs as well as other stereomers are studied by DFT calculations.