Chemical Biology Letters

Synthesis of novel imidazolo-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids as in vitro EGFR inhibitors

Jagan Mohan Reddy Velidandla, Shiva Kumar Koppula — Tue, 09 May 2023 00:00:00 +0000

The synthesis of new hybrid [1,2,4] triazolo [3,4-b][1,3,4]thiadiazine derivatives of imidazole (5a – 5m) and their structure determination using ¹HNMR, ¹³CNMR and mass spectral analysis were described. The in vitro cytotoxic activity of the compounds (5a – 5m) against three human cancer cell lines like MCF-7 and MDA-MB-231 (breast), alveolar (A-549) revealed that the compounds 5c, 5d, 5f, 5g, and 5m have shown greater activity against breast cancer cell lines than the remaining compounds. Compounds 5d and 5f have shown equipotent activity compared to the standard. In vitro tyrosine kinase EGFR inhibition assay for the same more potent compounds (5c, 5d, 5f, 5g, and 5m) revealed that 5f has more potent inhibiting power with an IC₅₀ value of 0.412±0.05 μM and 5d has equipotent inhibiting power with an IC₅₀ value of 0.436±0.07 μM compared to erlotinib (IC₅₀=0.423±0.03).

URN:NBN:sciencein.cbl.2023.v10.548

Bioorthogonal chemistry in the reproductive medicine

Pallav Sengupta, Sulagna Dutta, Bhupender S. Chhikara — Mon, 20 Mar 2023 00:00:00 +0000

The expanding field of bioorthogonal chemistry has demonstrated significant potential in advancing reproductive medicine. This comprehensive review elucidates the multifaceted applications of bioorthogonal chemistry across various aspects of reproductive medicine, including gamete biology, energetics and metabolic regulations of gametes, targeted drug delivery, detection and therapeutic of endometriosis and polycystic ovarian syndrome (PCOS), developments of diagnostic tools and new management approaches to reproductive cancers. In gamete biology, bioorthogonal reactions enable the precise manipulation and tracking of biomolecules within gametes, thus facilitating a deeper understanding of gamete development, maturation, and interaction. Bioorthogonal chemistry also plays an indispensable role in deciphering the intricate energetics and metabolic regulations governing gamete function and competence, consequently fostering the development of novel therapeutic interventions. Targeted drug delivery, utilizing bioorthogonal click chemistry, can improve the specificity and efficacy of pharmacological treatments in reproductive disorders, such as endometriosis and PCOS. In the realm of reproductive diagnostics, bioorthogonal chemistry engenders innovative tools for sensitive and noninvasive detection of reproductive anomalies. Finally, the integration of bioorthogonal strategies in studying reproductive cancers can uncover new molecular targets for therapeutics, leading to more effective treatment modalities. Collectively, this review highlights the paramount importance of bioorthogonal chemistry in revolutionizing reproductive medicine and fostering breakthroughs in the comprehension and management of reproductive health.

URN:NBN:sciencein.cbl.2023.v10.545

Natural O-6-methylguanine-DNA methyl transferase (MGMT) gene antagonist from Vaccinium oxycoccos: A new hope in Alzheimer’s therapeutics

Wed, 17 May 2023 00:00:00 +0000

Alzheimer's disease (AD) is a neurodegenerative illness with a complex pathobiology. The pathogenesis of Alzheimer's disease is majorly driven by mutation, overexpression and downregulation of β-amyloid (Aβ) gene that results in the aggregation of a β-amyloid (Aβ) protein within the neocortex. O-6-methylguanine-DNA methyl transferase (MGMT) gene coding for a DNA repair enzyme have found to play an important role in Alzheimer's disease. Some researchers have reported that Tau protein disintegration is directly tied to MGMT gene. An unavoidable, age-related increase in brain methylation of MGMT gene have shown to upregulate MGMT expression, resulting in Tau dysfunction. Due to the complex underlying pathology of Alzheimer disease (AD), treatment strategies are under extensive research as no new therapies have been approved by the US Food and Drug Administration (FDA) since 2003. Drug repositioning/molecular docking have appeared to be successful techniques to fasten the pharmacological research for AD treatment. In light to the same the study was aimed to evaluate various natural compounds from Vaccinium oxycoccos (cranberry) that are antagonist to MGMT gene. MGMT gene and Compounds structure was retrieved from PDB and PubChem databases and were screened for suitable interactions between them. Out of 23 compounds, four demonstrated strong binding affinity to MGMT gene and thus predicted to use as MGMT gene antagonist in developing the treatment for Alzheimer's disease (AD). These findings may be applicable to other degenerative diseases also where MGMT gene interactions have been involved.

URN:NBN:sciencein.cbl.2023.v10.549

Recent advancements in solubilization and Gastroretentive techniques for Oral Drug Delivery of Proton Pump inhibitors: A comprehensive review

Ritu Gulia, Sukhbir Singh, Sandeep Arora, Neelam Sharma — Fri, 14 Apr 2023 00:00:00 +0000

Proton pump inhibitors (PPIs) have been considered as safe and proficient therapeutic drugs enormously prescribed globally for management of acid-related disorders. PPIs have tendency to blockage proton pumps directly and therefore, considerably reduce gastric acid secretions. PPIs like lansoprazole, omeprazole, esomeprazole and dexlansoprazole are BCS class II medicines and meet challenge of inadequate drug dissolution in oral drug delivery and thus, require solubilization through various strategies like cyclodextrin inclusion complexes, nanosuspension, solid dispersion, microparticles, and solid dispersion pellets. PPIs also undergoes challenge of inadequate gastric residence time and therefore, development of gastroretentive drug delivery systems i.e. microbeads, microballoons, mucoadhesive and gastroretentive formulations, bilayer tablets, and super-porous hydrogel of PPIs has been crucial for acquiring vital local drug delivery in the gastrointestinal tract. This review provides comprehensive detail with regard to mechanism of action, pharmacokinetics/pharmacodynamics and physiochemical profile of PPIs. The primary objective of current review is recapitulation of research studies explored previously in order to overcome certain challenges in oral drug delivery of PPIs like low water solubility and inadequate gastric residence time.

URN:NBN:sciencein.cbl.2023.v10.546

Molecular docking-guided screening of phytoconstituents from Artemisia princeps as Allosteric Glucokinase Activators

Sun, 16 Apr 2023 00:00:00 +0000

Glucokinase (GK) occurs in pancreatic β-cells and liver cells. GK plays a crucial role in whole-body glucose homeostasis. GK is often referred to as a glucose sensor in the β-cells. Small molecule GK activators not only reduce fasting and basal blood glucose levels but also improve glucose tolerance. The present investigation was proposed to screen some phytoconstituents (from Artemisia princeps) as allosteric activators of the human GK enzyme using in silico molecular docking. A library of phytoconstituents reported in Artemisia princeps was evaluated for the prediction of drug-like properties by in silico approach. Molecular docking studies of the phytoconstituents with GK were performed using AutoDock vina in order to explore binding interactions between the phytoconstituents and GK enzyme followed by in silico prediction of toxicity of these phytoconstituents. The selected phytoconstituents showed good pharmacokinetic parameters for oral bioavailability and drug-likeness as contrived by Lipinski’s rule of five. Four compounds (rutin, 5,4'-dihydroxy-6,7,3'-trimethoxyflavone, daucosterol and methyl commate D) showed appreciable binding interactions with the allosteric site residues of the GK enzyme as per docking results. These screened phytoconstituents may serve as promising leads for further development of clinically useful and safe allosteric activators of the human GK enzyme.

URN:NBN:sciencein.cbl.2023.v10.547

Anti-prostate cancer and anti-EGFR activities of new Nilutamide-isoxazole hybrids

Mon, 20 Mar 2023 00:00:00 +0000

Herein, synthesis of new Nilutamide-isoxazoles (5a-5n) via Cu(I)-promoted one-pot reaction between 1-(but-3-yn-1-yl)-5,5-dimethyl-3-(4-nitro-3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione (3) and several aldehydes (4a-4n) in benign aq. ^tbutanol as key approach has been reported. The in vitro growth inhibition activity of all these compounds revealed that the majority of compounds were more active against DU-145 in comparison to PC3. Particularly, compounds 5f, 5h and 5k showed greater activity against DU-145 than the standard drug 5-Fluoro Uracil with IC₅₀ values <30 mM. whereas compound 5g showed comparable activity against DU-145 cell line with the positive control. The Epidermal growth factor receptor (EGFR) is well known to be expressed in DU-145 cancer cells, the most potent compounds 5f, 5h and 5k were then screened for their inhibitory potential against tyrosine kinase EGFR and found that compounds 5f and 5k showed remarkable inhibition with MIVs 93.4% and 91.3% respectively, while compound 5h displayed good inhibition (MIV = 84.6%) as compared to the Erlotinib.

URN:NBN:sciencein.cbl.2023.v10.542

Recent advances in Targeted Radionuclide therapy for Cancer treatment

Muskan Goel, Manish Kumar Mishra, Dhruv Kumar — Fri, 24 Mar 2023 00:00:00 +0000

In the last two decades, science has largely evolved in methodologies for cancer treatment, yet, the basic backbone of cancer treatment includes surgery, chemotherapy and radiation therapy. In oncology, radiation therapy was first used nearly a century ago but its basic principle is still in application, for example, radionuclide therapy (RNT) or targeted radionuclide therapy (TRT). TRT is effective in micro and macro metastasis and has an advantage due to low dose, high efficacy, easy targeting and treatment. The aim of this article is to overview the radionuclides, components of a TRT agent i.e., different types of radionuclides, vectors and chelators and then descriptively highlight the therapeutic potential of TRT agents in the treatment of various types of cancers, namely, breast cancer, metastatic bone pain, thyroid cancer, neuroendocrine neoplasm, prostate tumors, malignant lymphoma, brain tumors, and hepatocellular carcinoma.

URN:NBN:sciencein.cbl.2023.v10.544

Novel fluorinated piperazine based-amino acid derivatives as antiplasmodial agents: Synthesis, bioactivity and computational studies

Mon, 20 Mar 2023 00:00:00 +0000

A library of twenty novel analogues of fluorinated, N-(3-hydroxy-1-phenyl-4-(4-phenylpiperazin-1-yl)alkyl)amides containing different amino acids were synthesized and tested for the activity against Plasmodium falciparum (Pf3D7) culture. All the tested compounds showed TC₅₀ values >100 µM on HepG2 cells. Hit analogues 12c and 12e, displayed IC₅₀values in the sub-micromolar range, i.e., 0.696±0.0462 µM and 0.9377±0.0461 µM, respectively. Compounds 12c and 12e were also evaluated in combination with artemisinin, which slightly improved the activity of both the compounds with IC₅₀ values of 0.19 µM and 0.26 µM, respectively. For compounds 12c and 12e, in-silico studies were carried out. Overall, results obtained from both in vitro and in-silico studies, indicated that 12c and 12e were hit compounds with maximum potency.

URN:NBN:sciencein.cbl.2023.v10.543

Dietary Polyphenolics: Mechanistic role in control management of Diabetes and Metabolic Syndrome

Kunika Saini, Smriti Sharma, Vinayak Bhatia, Yousuf Khan — Wed, 15 Mar 2023 00:00:00 +0000

The search for an antidiabetic drug is going on three fronts: technological (for instance, development of an artificial pancreas), biological (such as pancreas and islet cell transplants), and pharmacological. Our review focusses on the role of polyphenolics in pharmacological research for T2DM. Being the most abundant antioxidants in human diets, dietary polyphenols have proven efficacy against a variety of diseases in both animal and human trials. Here, the authors present a review of advances in using polyphenols obtained from diet against diabetes and metabolic syndrome. Authors have discussed the role of polyphenols in disease management, and their sources. In addition to that, current knowledge of prevalent pathways of their action in cases of diabetes and metabolic syndrome have been discussed. The future directions and perspectives about diet polyphenols as a good alternative to first-line drug interventions have been included.

Role of Acetylcholinesterase (AChE) reactivators in the treatment of Organophosphorus poisoning: in vivo, in vitro, and in silico studies

Ratandeep, Ayushi, Garima, Laishram Saya Devi, Pooja — Fri, 27 Jan 2023 00:00:00 +0000

Chemical warfare agents, especially organophosphorus (OP) compounds, are known for their extreme toxicity causing inhibition of acetylcholinesterase (AChE) enzyme activity due to covalent phosphorylation. This leads to functional impairment of muscarinic nicotinic acetylcholine receptors, resulting in severe ill effects that ultimately lead to death. For OP poisoning, AChE reactivators play a crucial role in the treatment process. Among several AChE reactivators, Oxime reactivators are majorly employed for the treatment of OP intoxication, nevertheless, these are associated with certain drawbacks such as their toxic effects, low blood-brain barrier (BBB) penetration, less reactivation in the central nervous system (CNS), and inefficiency toward all nerve agents, and blocked AChE. As a result, new therapeutic strategies are required. Recent attempts are focused on the design and synthesis of uncharged oximes or non-oxime reactivators which can overcome the limitations of oxime-based reactivators. A novel class of non-oxime reactivators is gaining interest, including compounds like Mannich phenols, chloroquines, and some general bases. This review is a novel attempt to incorporate various possible oxime and non-oxime AChE reactivators for OP intoxication along with their in vitro, in vivo, and in silico studies.

URN:NBN:sciencein.cbl.2023.v10.538

In-vitro evaluation of synergism in antioxidant efficiency of Quercetin and Resveratrol

Fri, 20 Jan 2023 00:00:00 +0000

Plants serve as an excellent source of therapeutic molecules that help in medicinal treatments. The production of large amounts of pure phytocompounds from plant sources for human consumption and the nature of phytocompounds exhibiting toxicity issues at higher dosages lead to the challenge of increasing the therapeutic effect by using low dosages. This current study focuses on extracting two active antioxidant compounds, quercetin (Q) and resveratrol (R), from plant sources and evaluating their ability to exhibit antioxidant synergism through in vitro models. Quercetin and resveratrol were extracted using an ethanol-solvent extraction procedure from Allium cepa, and Vitis vinifera peels, respectively. The extracts were subjected to qualitative and quantitative analysis, column chromatography and then High-Performance Liquid chromatography for purification. DPPH, ABTS⁺, SOS, and cellular antioxidant assays evaluated the synergistic antioxidant activity of the quercetin and resveratrol complex. The results showed synergistic antioxidant efficacy values approximately as follows: 5.37 % in DPPH, 15.26 % in ABTS+, 11.99 % in SOS, and 19.13 % in cellular antioxidant assays when both molecules were used combinedly. The results promisingly pave the way for a new dimension in nutraceuticals formulation parameters which could trigger combined molecular usage to achieve better results at low dosages.

URN:NBN:sciencein.cbl.2023.v10.534

Deciphering the role of c-MET in Metabolic reprogramming of Head and Neck squamous cell Carcinoma via In Silico analysis

Sibi Raj, Brijesh Rathi, Pravesh Mehra, Shailendra Asthana, Dhruv Kumar — Fri, 20 Jan 2023 00:00:00 +0000

Targeting of epidermal growth factor receptors (EGFRs) and vascular endothelial growth factor receptors (VEGFRs) has become a major strategy for the control of head and neck cancer. c-MET, a receptor tyrosine kinase is known to be expressed in many cancers including the head and neck squamous cell carcinoma (HNSCC). The c-MET activity has been correlated with many signaling pathways that help the cancer cells to proliferate, migrate and invade into the normal, healthy tissues. The association of c-MET with glycolytic pathway in HNSCC has not been elucidated yet. Since, increased glycolysis has emerged as a major hallmark for cancer cell proliferation, targeting c-MET could bring an impact to inhibit HNSCC progression. In the present study we use various In-silico tools available to identify the association of c-MET with the major metabolic genes such as HK-II (Hexokinase-II), GLUT-1 (Glucose transporter-I), LDH-A (Lactate dehydrogenase-A), PFK-II (Phosphofructokinase-II) and MCT-1 (Monocarboxylate transferase-1) in HNSCC patient datasets available from The Cancer Genome Atlas (TCGA). Protein networking analysis was used to determine the correlation of c-MET with the metabolic genes. Retrieved sequenced data pathway analysis gives the network of genes associated in the activation of glycolytic pathway. Gene ontology and Enrichr studies provide an insight into c-MET activity in metabolism through molecular, functional and pathway basis in HNSCC. Furthermore, we also have shown a negative correlation of c-MET with immune cell infiltration, suggesting c-MET might have a role in immune suppression in HNSCC patients. Further validation on this study could possibly make c-MET as a potential target to inhibit HNSCC.

URN:NBN:sciencein.cbl.2023.v10.532

Regioselective synthesis of indole-thiazolidine-2,4-dione coupled isoxazoles as in vitro tubulin polymerization inhibitors

Sunitha Boda, Ravinder Manchal — Mon, 02 Jan 2023 00:00:00 +0000

Herein we synthesized new indole-thiazolidine-2,4-dione coupled isoxazoles (7a-n) via simple reactions like N-propargylation, Knoevenagel condensation and copper (I) catalysed one pot regioselective reactions. All the newly synthesized compounds were characterized by 1H-NMR, 13C-NMR and Mass spectra and they were screened for in vitro anticancer activity against three human cancer cell lines like A549 (lung), MCF-7 (breast), and SKOV3 (ovarian) using MTT assay and etoposide was used as the standard drug. As per the results the compounds 7e, 7f and 7g where shown selectivity towards A549 cell line with IC₅₀ values of 5.27 µM, 3.14 µM and 6.25 µM respectively and they are high active than etoposide. Further in vitro tubulin polymerization assay on three potent compounds (7e, 7f and 7g) revealed that compounds 7e and 7f have exhibited potency than standard combretastatin A-4 with IC₅₀ values 0.82 and .044 mM respectively.

URN:NBN:sciencein.cbl.2023.v10.531

In Silico Docking Studies of Yucca gloriosa L. Phytoconstituents with TNF-α, IL-6 and IL-13 Receptor Against Asthma

Sat, 24 Dec 2022 00:00:00 +0000

Yucca gloriosa L. has been comprehensively assessed in vitro and in vivo for its action against asthma. Y. gloriosa L. is a rich source of phenolic compounds such as gloriosaols A-E and yuccaols A-E, which exhibit potent antioxidant activity. Gloriosaols A-E and yuccaols A-E are structurally related to corticosteroids. The current study describes the in silico docking of some important anti-asthmatic phytoconstituents from the plant Y. gloriosa L. with molecular targets of asthma. Toward the recognition of the binding methods of these pharmacologically dynamic components, molecular modelling studies were carried out with target proteins, i.e., interleukin (IL)-6 (1N26), IL-13 (3LB6) and TNF-α (2AZ5), using in silico molecular docking. The components demonstrated encouraging binding interactions with the amino acid residues at the active sites of these proteins, authenticating their verified efficiency as anti-asthmatic agents. The current research, in addition, provides insight into the possible herbal drug-receptor interaction and synthetic drug montelukast sodium receptor interaction, for the possible management of asthma.

URN:NBN:sciencein.cbl.2023.v10.509

Synthesis, characterization and anticancer evaluation of new 1H-naphtho[2,3-d]imidazole-4,9-dione-1,2,4-oxadiazole hybrids

Sasidhar Alluru, Sailaja BBV, Arani Pal — Wed, 11 Jan 2023 00:00:00 +0000

New series of 1H-naphtho[2,3-d]imidazole-4,9-dione-1,2,4 oxadiazoles (10a-10l) synthesized using NH₂OH.HCl/Et₃N and POCl₃/DMF (Vilsmeier reagent) mediated one-pot reaction between 2-(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-1-yl)acetonitrile and several aromatic carboxylic acids as key approach have been reported here. All synthesized compounds were screened for the in vitro cytotoxicity against three human cancer cell lines such as A549, PC3, and MCF-7. Three compounds (10d, 10f and 10k) exhibited superior activity than the standard etoposide against all the cell lines with IC₅₀ values <2 μM. Finally, molecular docking studies revealed the important binding interactions of potent compounds 10d, 10f and 10k with the α, β-tubulin (PDB ID-1SA0).

URN:NBN:sciencein.cbl.2023.v10.506