Beneficial Effects of PIN1 Inhibition on Diabetes Mellitus: A Concise Review.

Type 2 diabetes mellitus is a long-term medical illness in which the body either becomes resistant to insulin or fails to produce it sufficiently. Mostly, combinatorial therapy is required to control blood glucose levels. However, combinatorial therapy has detrimental side effects. The prevalence of the cases and subsequent increases in medical costs of the same intimidate human health globally. While there have been a lot of studies focused on developing diabetic regimens that work to lower blood glucose levels, their effectiveness is short-lived because of unfavorable side effects, such as weight gain and hypoglycemia. In recent years, the PIN1 (protein interacting with NIMA) enzyme has attracted the attention of researchers. Previous studies suggested that PIN1 may act on the various substrates that are involved in the progression of T2DM and also help in the management of diabetes-related disorders. Thus, the focus of the current review is to examine the correlation between PIN1, T2DM and its related disorders and explore the possibility of developing novel therapeutic targets through PIN1 inhibition.

Neuroprotective potential of pyrazole benzenesulfonamide derivative T1 in targeted intervention against PTZ-induced epilepsy-like condition in in vivo zebrafish model.

Epilepsy is a chronic neurological disease characterized by a persistent susceptibility to seizures. Pharmaco-resistant epilepsies, impacting around 30 % of patients, highlight the urgent need for improved treatments. Neuroinflammation, prevalent in epileptogenic brain regions, is a key player in epilepsy, prompting the search for new mechanistic therapies. Hence, in this study, we explored the anti-inflammatory potential of pyrazole benzenesulfonamide derivative (T1) against pentylenetetrazole (PTZ) induced epilepsy-like conditions in in-vivo zebrafish model. The results from the survival assay showed 79.97 ± 6.65 % at 150 µM of T1 compared to PTZ-group. The results from reactive oxygen species (ROS), apoptosis and histology analysis showed that T1 significantly reduces cellular damage due to oxidative stress in PTZ-exposed zebrafish. The gene expression analysis and neutral red assay results demonstrated a notable reduction in the inflammatory response in zebrafish pre-treated with T1. Subsequently, the open field test unveiled the anti-convulsant activity of T1, particularly at a concentration of 150 µM. Moreover, both RT-PCR and immunohistochemistry findings indicated a concentration-dependent potential of T1, which inhibited COX-2 in zebrafish exposed to PTZ. In summary, T1 protected zebrafish against PTZ-induced neuronal damage, and behavioural changes by mitigating the inflammatory response through the inhibition of COX-2.

Furan based synthetic chalcone derivative functions against gut inflammation and oxidative stress demonstrated in in-vivo zebrafish model.

Inflammatory Bowel Disease (IBD) is a group of persistent intestinal illnesses resulting from bowel inflammation unrelated to infection. The prevalence of IBD is rising in industrialized countries, increasing healthcare costs. Whether naturally occurring or synthetic, chalcones possess a broad range of biological properties, including anti-inflammatory, anti-microbial, and antioxidant effects. This investigation focuses on DKO7 (E)-3-(4-(dimethylamino)phenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one, a synthesized chalcone with potential anti-inflammatory effects in a zebrafish model of intestinal inflammation induced by Dextran sodium sulfate (DSS). The in vitro study displayed dose-dependent anti-inflammatory as well as antioxidant properties of DKO7. Additionally, DKO7 protected zebrafish larvae against lipid peroxidation, reactive oxygen stress (ROS), and DSS-induced inflammation. Moreover, DKO7 reduced the expression of pro-inflammatory genes, including TNF-α, IL-1ß, IL-6, and iNOS. Further, it reduced the levels of nitric oxide (NO) and lactate dehydrogenase (LDH) in the intestinal tissues of adult zebrafish and increased the levels of antioxidant enzymes such as Catalase (CAT) and superoxide dismutase (SOD). The protective effect of DKO7 against chemically (or DSS) induced intestinal inflammation was further verified using histopathological techniques in intestinal tissues. The furan-based chalcone derivative, DKO7, displayed antioxidant and anti-inflammatory properties. Also, DKO7 successfully reverses the DSS-induced intestinal damage in zebrafish. Overall, this study indicates the ability of DKO7 to alleviate DSS-induced gut inflammation in an in-vivo zebrafish.

Role and mechanistic actions of protein kinase inhibitors as an effective drug target for cancer and COVID.

Kinases can be grouped into 20 families which play a vital role as a regulator of neoplasia, metastasis, and cytokine suppression. Human genome sequencing has discovered more than 500 kinases. Mutations of the kinase itself or the pathway regulated by kinases leads to the progression of diseases such as Alzheimer's, viral infections, and cancers. Cancer chemotherapy has made significant leaps in recent years. The utilization of chemotherapeutic agents for treating cancers has become difficult due to their unpredictable nature and their toxicity toward the host cells. Therefore, targeted therapy as a therapeutic option against cancer-specific cells and toward the signaling pathways is a valuable avenue of research. SARS-CoV-2 is a member of the Betacoronavirus genus that is responsible for causing the COVID pandemic. Kinase family provides a valuable source of biological targets against cancers and for recent COVID infections. Kinases such as tyrosine kinases, Rho kinase, Bruton tyrosine kinase, ABL kinases, and NAK kinases play an important role in the modulation of signaling pathways involved in both cancers and viral infections such as COVID. These kinase inhibitors consist of multiple protein targets such as the viral replication machinery and specific molecules targeting signaling pathways for cancer. Thus, kinase inhibitors can be used for their anti-inflammatory, anti-fibrotic activity along with cytokine suppression in cases of COVID. The main goal of this review is to focus on the pharmacology of kinase inhibitors for cancer and COVID, as well as ideas for future development.

Deuterated driven new chemical entities: An optimistic way to improve therapeutic efficacy.

In organic chemistry, the use of deuterium exchange as a tool to study the mechanism of chemical reaction has been well explored. Since two decades, the research focus on deuterated bioactive molecules has been gaining attention for investigating the therapeutic potential of deuterium replacement in a chemical structure. Recently, Food Drug Administration (FDA) approved the first deuterium-labeled drug "deutetrabenazine", and notified the deuterated drugs as new chemical entities (NCEs). Henceforth, the deuterium substitution driven structure activity relationship, preclinical pharmacokinetics, and toxicity studies were much initiated. Deuteration of a bioactive molecule often results in improved therapeutic efficacy due to the altered pharmacokinetic profile. This review provides a conceptual framework on the importance of deuterium atom in chemical structure of a drug, and its biological value in improved physiochemical properties, pharmacokinetics, biological target interaction, diagnosis, and toxicity. In addition, this review concisely updated the recent deuteration methods, chemical stability, challenges in drug development, deuterium-based imaging in diagnosis, and selected synthetic scheme of deuterated molecules.

An overview of mechanism and chemical inhibitors of shikimate kinase.

Tuberculosis is a highly infectious disease other than HIV/AIDS and it is one of the top ten causes of death worldwide. Resistance development in the bacteria occurs because of genetic alterations, and the molecular insights suggest that the accumulation of mutation in the individual drug target genes is the primary mechanism of multi-drug resistant tuberculosis. Chorismate is an essential structural fragment for the synthesis of aromatic amino acids and synthesized biochemically by a number of bacteria, including Mycobacterium tuberculosis, utilizing the shikimate pathway. This shikimate kinase is the newer possible target for the generation of novel antitubercular drug because this pathway is expressed only in mycobacterium and not in Mammals. The discovery and development of shikimate kinase inhibitors provide an opportunity for the development of novel selective medications. Multiple shikimate kinase inhibitors have been identified via insilico virtual screening and related protein-ligand interactions along with their in-vitro studies. These inhibitors bind to the active site in a similar fashion to shikimate. In the current review, we present an overview of the biology and chemistry of the shikimate kinase protein and its inhibitors, with special emphasis on the various active scaffold against the enzyme. A variety of chemically diversified synthetic scaffolds including Benzothiazoles, Oxadiazoles, Thiobarbiturates, Naphthoquinones, Thiazoleacetonitriles, Hybridized Pyrazolone derivatives, Orthologous biological macromolecule derivatives, Manzamine Alkaloids derivatives, Dipeptide inhibitor, and Chalcones are discussed in detail. These derivatives bind to the specific target appropriately proving their potential ability through different binding interactions and effectively explored as an effective and selective Sk inhibitor.Communicated by Ramaswamy H. Sarma.

Molecular insights into benzene sulphonamide substituted diarylpyrazoles as cyclooxygenase-2 inhibitor and its structural modifications.

Quantitative Structure Activity Relationship (QSAR) is one of the realistic and most successful methods for drug design in optimizing a lead. A series of forty-four molecules from diarylpyrazole benzene sulphonamide derivatives with their cyclooxygenase-2 inhibitory activity were subjected to qsar studies using QSARINS software. The significant two descriptor qsar model generated showed correlation coefficient of cross validation leave one out (Q2LOO)=0.5565, coefficient of determination (R2)=0.6530, (R2ext)=0.8225, cross validation leave many out (Q2LMO)=0.5201, Concordance Correlation Coefficient (CCCcv)=0.7262, CCCtr=0.7901, and CCCext=0.8930. The descriptor 3D Molecular Representations of Structures based on Electronic diffraction (3D-MoRSEC-6) weighted by atomic charges, where 6 is scattering parameter and Geary Autocorrelation-lag3/weighted by atomic Sanderson electronegativities (GATSe3) revealed that the atomic charges and spatial autocorrelation play a key role in Cyclooxygenase-2 inhibitory (COX-2) activity. New lead molecules were designed based on key structural findings and predicted for their COX-2 inhibitory activity using the developed two-descriptor model. Molecular docking studies were carried out for the best-designed molecules using Autodock 4.2.6 along with supportive in silico absorption, distribution, metabolism, excretion, and toxicity predictions. Both the hydrophilic as well as hydrophobic parts of the residues of active site regions interacted with best predicted active compounds. The study suggests crucial properties and key interactions that are essential for potent enzyme inhibition and finds this series as a promising lead for further development as novel cyclooxygenase agents. Communicated by Ramaswamy H. Sarma.

Identification of novel scaffold using ligand and structure based approach targeting shikimate kinase.

Tuberculosis (TB) remains a major global health problem. It causes ill-health among millions of people each year and rank as the second leading cause of death from an infectious disease worldwide, after the human immunodeficiency virus (HIV). Shikimate kinase is one of the major enzymes targeted for TB. Most approaches to overcome TB were based on synthesis and screening of a known compounds to obtain a few representatives with desired potency. In this study, we have applied a virtual screening approach which combines ligand- and structure-based approaches to screen a large library of compounds as a starting point for the identification of new scaffolds for the development of shikimate kinase inhibitors. The combined approach has identified 2 new scaffolds as potential inhibitors of shikimate kinase. To prove the approach, few of the molecules and their derivatives, a total of 17 compounds, were synthesized. The compounds were tested for biological activity and shows moderate activity against shikimate kinase. The shikimate kinase enzyme inhibition study reveals that the compounds showed inhibition (IC50) at concentrations of 50 µg/mL (Compounds 21, 22, 24, 25, 26, 27, 30, 32, 34) and 25 µg/mL (14, 19, 23, 31, 33).

Mycothiol: a promising antitubercular target.

Tuberculosis (TB) is the world's second commonest cause of death next to HIV/AIDS. The increasing emergence of multi drug resistance and the recalcitrant nature of persistent infections pose an additional challenge for the treatment of TB. Due to the development of resistance to conventional antibiotics there is a need for new therapeutic strategies to combat M. tuberculosis. One such target is Mycothiol (MSH), a major low molecular-mass thiol in mycobacteria, an important cellular anti-oxidant. MSH is present only in actinomycetes and hence is a good target. This review explores mycothiol as a potential target against tuberculosis and various research ongoing worldwide.

Design, synthesis, and evaluations of antifungal activity of novel phenyl(2H-tetrazol-5-yl)methanamine derivatives.

Fungal infections pose a continuous and serious threat to human health and life. The intrinsic resistance has been observed in many genera of fungi. Many fungal infections are caused by opportunistic pathogens that may be endogenous (Candida infections) or acquired from the environment (Cryptococcus and Aspergillus infections). So, new therapeutic strategies are needed to combat various fungal infections. Fluconazole shows good antifungal activity with relatively low toxicity and is preferred as first line antifungal therapy, but it has suffered from severe drug resistance. So, there is a need to design novel analogues by modification of fluconazole-like structure. A novel series of phenyl(2H-tetrazol-5-yl)methanamine derivatives were synthesized by reaction of α-amino nitrile with sodium azide and ZnCl2 in presence of isopropyl alcohol. They were evaluated for antifungal activity against Candida albicans and Aspergillus niger and subjected to docking study against 1EA1.

The biology and chemistry of hyperlipidemia.

Coronary arterial diseases are responsible for more deaths than all other associated causes combined. Elevated serum cholesterol levels leading to atherosclerosis can cause coronary heart disease (CHD). Reduction in serum cholesterol levels reduces the risk for CHD, substantially. Medicinal chemists all around the world have been designing, synthesizing, and evaluating a variety of new bioactive molecules for lowering lipid levels. This review summarizes the disorders associated with elevation of lipids in blood and the current strategies to control them. The emphasis has been laid in particular on the new potential biological targets and the possible treatments as well as the current ongoing research status in the field of lipid lowering agents.