Category: Medicinal Chemistry

Platinum-based chemotherapeutics inflict a spectrum of DNA damage, including DNA adducts, DNA-protein crosslinks (DPCs), and interstrand crosslinks (ICLs) to variable extents. These diverse lesions may contribute to the overall toxicity of these therapeutic agents. Nonetheless, a gap exists in comparative studies elucidating the specific DNA damage responsible for their toxicity. Therefore, we exposed MRC5SV cells to equitoxic doses (LD₁₀) of cisplatin (cisPt) and oxaliplatin (L-OHP) and systematically examined the induction of DPCs, ICL, and protein damage. Our findings suggest that DPCs emerge as the crucial cytotoxic DNA damage for both cisPt and L-OHP, highlighting their central role in the mechanism of action driving the cytotoxicity of platinum-based therapeutics. Both drugs show induction of ICLs as computed by the unique sensitivity of Fanconi anemia cells to the drugs. Additionally, both cisPt and L-OHP didn’t show protein damage as indicated by the absence of TRX1 oxidation post-treatment. Overall, our results underscore the critical involvement of DPCs in the toxicity of platinum-based drugs, emphasizing the importance of DPCs as potential cancer therapeutic targets.

URN:NBN:sciencein.cbl.2024.v11.663

Synthesis of 9-(4-bromophenyl)-6 aryl-[1,2,4]triazolo[4,3-a][1,8]naphthyridine-2-carbonitrile (4a-j) from 7-(2-(4bromobenzylidene)hydrazinyl)-6-aryl-1,8-naphthyridine-2-carbonitrile (3) oxidized with chloramines-T in methanol under microwave irradiation is a straight forward and very efficient process. Very high yields and excellent purities of the products were achieved. Elemental analysis, IR, ¹H NMR, ¹³C NMR and Mass spectroscopy are used to characterize the produced compounds. All synthesized compounds were tested for their antimicrobial efficacy and found moderately active against different types of bacterial and fungal strains in comparison with Streptomycin, Nystatin.

URN:NBN:sciencein.cbl.2024.v11.664

Antimicrobial resistance (AMR) poses a significant threat to global health. It makes treating bacterial infections increasingly difficult. AMR arises from various mechanisms of antibiotic resistance including enzymatic inactivation, target alteration, efflux pumps, and decreased permeability. The limited and often ineffective treatments relying on antibiotics and their combinations result in increased morbidity and mortality. Therefore, it is essential to explore alternative methods for combating the challenge of AMR. In recent years, there has been a notable shift towards precision medicine in the battle against AMR. Precision medicine, characterized by its focus on individualized treatment tailored to patients’ specific genetic makeup, offers a paradigm shift in addressing AMR challenges. By pinpointing molecular targets responsible for infection, precision medicine enables more targeted and effective therapies, minimizing the risk of antimicrobial resistance development. Precision medicine can provide an alternative option to combat AMR by focusing on targets responsible for the infection. Bacteriophages and antimicrobial peptides (AMPs) are groups of antimicrobials that can serve as novel alternatives to antibiotics for combating the global antibiotic resistance challenge. They have the potential to be used as targeted therapy. Despite challenges such as limited host range, which refers to the specific bacteria they can infect, and regulatory concerns related to their approval and usage, bacteriophages have proven effective against bacteria causing infections. Meanwhile, AMPs provide a potential treatment approach against antibiotic-resistant bacteria due to their low molecular weight and broad-spectrum antimicrobial activity. AMPs can serve as a first line of defense against microorganisms. When used alone or combined with other biomaterials to increase therapeutic action, they can serve as a first line of defense against microorganisms. This review article aims to provide a comprehensive overview of the current understanding and clinical potential of bacteriophages and AMPs as alternatives to conventional antibiotics in addressing the pressing challenge of AMR.

URN:NBN:sciencein.cbl.2024.v11.662

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

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.

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

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

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

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

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