Synthesis and biological evaluation of Trifluoromethoxyphenyl Indole Carboxamide analogs, ADME and toxicity prediction

Synthesis and biological evaluation of Trifluoromethoxyphenyl Indole Carboxamide analogs, ADME and toxicity prediction

We report synthesis, ADME profile, and biological evaluation of new analogues as effective Anticancer Agents. Trifluoromethoxyphenyl indole-5-carboxamide analogues (4a-4m) were developed as a class of strong inhibitors of BCR-ABL1 kinase. The compounds (4c, 4e, and 4m) showed good anticancer activity in cancer cell lines such as MCF7, MV411 and K562 with IC50 values of 1.4 µM, 1.7 µM, and 1.1 µM, respectively. In human liver microsomes, these substances likewise displayed a favorable ADME profile, good solubility, and minimal clearance. In an oncology program these analogues offer a promising beginning for the development of BCR-ABL1 kinase inhibitors.

URN:NBN:sciencein.cbl.2024.v11.660

Synthesis and biological evaluation of Trifluoromethoxyphenyl Indole Carboxamide analogs, ADME and toxicity prediction – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a660

Chemical Biology Letters

Exploring Small-Molecule Inhibitors Targeting MAPK Pathway Components: Focus on ERK, MEK1, and MEK2 Kinases in Cancer Treatment

Exploring Small-Molecule Inhibitors Targeting MAPK Pathway Components: Focus on ERK, MEK1, and MEK2 Kinases in Cancer Treatment

Mitogen-activated protein kinases (MAPKs), also known as extracellular signal regulated kinases (ERKs), are found in numerous signal transduction pathways and are triggered by protein kinase cascades. This article will review the present state of MAPK pathway inhibitors, with an emphasis on the characteristics of tiny molecule blockers of the p38, MEK1, and MEK2 protein kinases. Many of these inhibitors have showed potential in experimental animal models of disease, and they are now being investigated in people for inflammatory and cancer diseases. Clinical trials are currently evaluating targeting a subset of cellular signaling cascades and signaling cascades that control pleiotropic cellular activity. These activities will have far-reaching consequences for the management of a wide range of disorders. The Ras-Raf-MEK-ERK (ERK) pathway, on the other hand, is a clear therapeutic target because it is a common downstream route for a range of critical growth factor tyrosine kinase receptors that are frequently changed or overexpressed in human malignancies. Several new medicines that target this route have been discovered and are currently being tested in clinical studies. BAY 43-9006 is one of the most intriguing new agents. Although it was initially created as a Raf kinase inhibitor, it also has the ability to target Flt-3, c-Kit, and VEGFR-2, which helps to explain its antiproliferative and antiangiogenic characteristics. The ERK signaling system in normal and malignant tissue will be discussed in this paper, with a focus on emerging treatments that target the ERK cascade at the Raf kinase level.

Exploring Small-Molecule Inhibitors Targeting MAPK Pathway Components: Focus on ERK, MEK1, and MEK2 Kinases in Cancer Treatment – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a659

Chemical Biology Letters

Remodeling of membrane lipid homeostasis in azole resistant isolates of Candida albicans

Remodeling of membrane lipid homeostasis in azole resistant isolates of Candida albicans

Azole resistance mechanisms in Candida albicans infections majorly focus around the alteration of target enzymes, overexpression of efflux pump proteins, and changes in lipid metabolism. Our earlier lipidomic studies have linked changes in cellular lipid compositions to drug susceptibilities and phenotypic defects. This study investigates the relationship between whole cell and membrane lipid profiles in isogenic drug-susceptible and resistant isolates of C. albicans. We have examined the fatty acid and sterol snapshot lipidomics in whole cells, plasma membrane, and lipid rafts. Correlations were discovered between these lipid compositions and the observed drug resistance in C. albicans. Although the correlations drawn from cellular and plasma membrane data corroborate, understanding plasma membrane and suborganellar (rafts in this case) lipid changes may provide better insights into their roles in efflux pump activities and localization, and drug susceptibilities.

URN:NBN:sciencein.cbl.2024.v11.658

Remodeling of membrane lipid homeostasis in azole resistant isolates of Candida albicans – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a658

Chemical Biology Letters

Design, synthesis and biological evaluation of novel sulfamoyl benzamides as allosteric activators of human glucokinase

Design, synthesis and biological evaluation of novel sulfamoyl benzamides as allosteric activators of human glucokinase

Glucokinase (GK) activators, which target the GK enzyme, are an emerging class of therapeutics with promising effects against diabetes. The objective of this work was to create a new group of sulfamoyl benzamide derivatives with the ability to activate GK and evaluate their effectiveness in treating diabetes. From benzoic acid, several compounds containing sulfamoyl benzamide scaffold were synthesized and evaluated for their ability to activate GK in an in vitro enzymatic experiment. In silico docking analyses were employed to explore how the most suitable arrangements in the allosteric area of the GK enzyme interact during binding. The effectiveness of the identified substances in reducing high blood sugar levels was assessed using the oral glucose tolerance test (OGTT) in healthy rats. This evaluation was based on the results of laboratory tests on enzymes and in silico simulations. One of the most active compounds from the antihyperglycemic assay was then tested for its antidiabetic effects in an induced diabetic rat OGTT assay. The in vitro GK activation was best among compounds 1, 6, and 8 (activation fold: 2.03-2.09). In the OGTT assay (normal rats), compounds 1 and 6 showed promising antihyperglycemic activity. In vivo antidiabetic assay confirmed the consistency with in silico and in vitro outcomes. The newly synthesized derivatives of sulfamoyl benzamide have the potential to be used as a basis for the development of further GK activators that are both safe and efficacious and can be administered orally. These activators may be used as therapeutic agents to treat type 2 diabetes.

URN:NBN:sciencein.cbl.2024.v11.657

Design, synthesis and biological evaluation of novel sulfamoyl benzamides as allosteric activators of human glucokinase – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a657

Chemical Biology Letters

Molecular pathways with role to play in oral cancer: A mini-review

Molecular pathways with role to play in oral cancer: A mini-review

Oral cancer is the sixth most prevalent type of cancer worldwide and third in India out of the different cancer types identified. Mouth and oral cancers collectively refer to cancers of the buccal cavity, lips, oropharynx, hypopharynx, and larynx. Genetic anomalies, the upregulation of several proteins, the deregulation of tumor-suppressive and oncogenes, and risk factors like alcohol and tobacco consumption are a few examples of the known irregularities that contribute to the development of oral cancer through the accumulation of various carcinogenic substances. Oral cancer is caused and developed by multiple molecular and cellular pathways such as PI3K/AKT/mTOR, Ras-Raf-MEK-ERK pathway, Wnt signaling, NF-κB pathway, Hippo pathway, etc. In addition, various genes including TP53, PTEN, CDKN2A, HRAS, PIK3CA, NOTCH1, IRF6, TP63, etc. are also involved in this malignancy. Therefore, it is crucial to have a deep understanding of these pathways to properly understand the development of oral cancer. This short review focuses on compiling together various signaling and molecular pathways accountable for oral carcinoma development.

URN:NBN:sciencein.cbl.2024.v11.652

Molecular pathways with role to play in oral cancer: A mini-review – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a652

Chemical Biology Letters

Synthesis of Indole-Oxadiazole coupled isoxazole hybrids as potent EGFR targeting anticancer agents

Synthesis of Indole-Oxadiazole coupled isoxazole hybrids as potent EGFR targeting anticancer agents

The synthesis of new indole-oxadiazole coupled isoxazole hybrids (6a–o) synthesized by the Cu(I)-catalyzed reaction of in situ generated nitrile oxides with 3-(3,5-dichloro-4-methoxyphenyl)-5-(1-(prop-2-yn-1-yl)-1H-indol-3-yl)-1,2,4-oxadiazole in good yields have been reported here. The chemical structures of all newly synthesized hybrids were confirmed by 1H-NMR, 13C-NMR, and Mass spectra. All synthesized compounds were screened for their in vitro cytotoxicity against two breast cancer cell lines MCF-7 and MDA-MB-231 respectively. All the derivatives were more active against MCF7 than MDA-MB-231 cancer cells and few compounds showed better activity than the standard erlotinib. The ability of more potent compounds to inhibit EGFR tyrosine kinase, one of the key enzymes involved in breast carcinomas was evaluated by in vitro enzymatic assay and it was found that the compound (6g) and (6m) had more inhibitory activity IC50 values 0.311±0.05 and 0.203±0.03 mM than erlotinib (IC50=0.421±0.03 mM).

URN:NBN:sciencein.cbl.2024.v11.651

Synthesis of Indole-Oxadiazole coupled isoxazole hybrids as potent EGFR targeting anticancer agents – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a651

Chemical Biology Letters

Synthesis of 1,4-disubstituted-1,2,3-Triazole derivatives for investigation of inhibition and molecular docking studies against Xanthine Oxidase

Synthesis of 1,4-disubstituted-1,2,3-Triazole derivatives for investigation of inhibition and molecular docking studies against Xanthine Oxidase

This study evaluates the inhibition effect of new 1,4-disubstituted-1,2,3-triazoles against Xanthine Oxidase supplemented by molecular modelling. Nine compounds of 1,4-disubstituted-1,2,3-triazoles by Sharpless’s approach have been synthesized in this report. The structures of the synthesized compounds were characterized using FT-IR, 1H and 13C-NMR and Mass spectroscopies Among these synthesized molecules (5-bromothiophen-2-yl)(1-(3-fluorobenzyl)-1H-1,2,3-triazole-4-yl)methanone (9f) and (5-Bromothiophen-2-yl(1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-yl)methanone (9h) showed better activity against Xanthine oxidase (XO) compared to allopurinol. In the light of the XO inhibition results, triazoles having of ketone moiety (9f-i) were found to be more active than triazoles of ketone-free (9a-e). These results were supported by docking models. The docking calculations of the target XO with nine available compounds showed good binding energies with favourable binding interactions. These findings were particularly evident that 9f (BE -7.29 kcal/mol) and 9h (BE -7.59 kcal/mol) are represented encouraging higher inhibition properties towards xanthine oxidase (XO), compared to allopurinol as a reference compound. Significant binding energies and interactions obtained by performing the docking studies are demonstrated, in particular, that the compounds 9f and 9h may be more potential bio compounds than the positive compounds, allopurinol, and febuxostat.

URN:NBN:sciencein.cbl.2023.v10.628

Synthesis of 1,4-disubstituted-1,2,3-Triazole derivatives for investigation of inhibition and molecular docking studies against Xanthine Oxidase – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a628

Chemical Biology Letters

Impact of resistin gene polymorphism on insulin resistance and Type 2 diabetes in Iraqi Babylon province patients

Impact of resistin gene polymorphism on insulin resistance and Type 2 diabetes in Iraqi Babylon province patients

Resistin is cysteine-rich polypeptide produced by adipocytes and macrophages. This study aims to assess the role of resistin and its gene polymorphisms (rs-34861192 G>A, NG-023447 C>G) as potential link between obesity and insulin resistance in the development of T2DM. Blood samples were collected from 120 participants (60 control are divided into 30 normal weight and 30 obese without T2DM) and (60 patients of Type 2 dm DM) are divided into 30 normal weight and 30 obese). Resistin and insulin levels were increased significantly in the patients’ group (p<0.05). Gene analysis indicated that rs-34861192 was associated significantly (P<0.01) with T2DM in dominant, recessive, and co-dominant models. The rs-34861192 AA genotype showed a significant difference in normal-weight and obese T2DM compared to control (P<0.001) only. The significant difference of GG genotype in normal-weight patients than control exclusively. In the diabetic patients, mutant genotype (AA) of rs34861192 was associated with circulating resistin level. The expression of retn gene was high. Genotype AA of rs- 34861192 was correlated positively with folding change. Mutant AA of rs-34861192 G>A plays an important role in development of T2DM through its effect on resistin levels in the circulation that considered as a major factor for developing T2DM.

URN:NBN:sciencein.cbl.2023.v10.629

Impact of resistin gene polymorphism on insulin resistance and Type 2 diabetes in Iraqi Babylon province patients – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a629

Chemical Biology Letters

Synthesis of novel phthalimide-based piperazine conjugated analogs as anti-malarial agents

Synthesis of novel phthalimide-based piperazine conjugated analogs as anti-malarial agents

In the present report, we synthesized twelve novel phthalimide analogs and evaluated for antiplasmodial efficacy on Plasmodium falciparum culture. Two molecules exhibited significant inhibition percentages at 1 µM concentration without any apparent cytotoxicity on HepG2 cells. Inhibitory concentration (IC50) for both the hit compounds 6d and 8a was observed in micromolar range, 1.20 µM and 1.66 µM, respectively. Extensive in silico studies conducted indicate plasmepsin IX as a possible target for inhibitory activity of the reported molecules.

URN:NBN:sciencein.cbl.2023.v10.627

Synthesis of novel phthalimide-based piperazine conjugated analogs as anti-malarial agents – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a627

Chemical Biology Letters

Small-molecules against Oxidative stress mediated Neurodegenerative diseases

Small-molecules against Oxidative stress mediated Neurodegenerative diseases

Neurodegenerative diseases, marked by the gradual deterioration of neuronal structure and function, impose a significant burden on global healthcare systems. Oxidative stress, resulting from an imbalance between reactive oxidant production and cellular antioxidant defense, is believed to play a significant role in the development of various neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Recently, there has been a growing interest in exploring small compounds as potential therapeutic agents to counteract oxidative stress. In addition to highlighting the potential of small molecules to prevent oxidative stress-mediated neuronal damage, this article provides an overview of the function of oxidative stress in neurodegenerative illnesses. Targeting numerous oxidative stress-related pathways, a number of small molecules, including both natural and synthetic antioxidants, have shown promise for neuroprotective benefits. These substances neutralise reactive oxidants, boost endogenous antioxidant defences, reduce inflammation, alter mitochondrial function, and encourage neurotrophic growth.

URN:NBN:sciencein.cbl.2023.v10.626

Small-molecules against Oxidative stress mediated Neurodegenerative diseases – https://pubs.thesciencein.org/journal/index.php/cbl/article/view/a626

Chemical Biology Letters