A novel role for nonactin: interfering with G-quadruplex in RET-driven medullary thyroid cancer.

Background: Medullary Thyroid Carcinoma (MTC) is closely associated with mutations in the RET proto-oncogene, placing the activated RET protein at the center of MTC pathogenesis. Existing therapeutic solutions, primarily tyrosine kinase inhibitors such as selpercatinib, vandetanib, and cabozantinib, have shown moderate efficacy but are accompanied by increased risks of side effects and resistance. This study unveils a promising avenue using nonactin, a compound historically recognized for its antibacterial properties, targeting the G-quadruplex interactions within the RET proto-oncogene.

A pyrazolopyridine as a novel AhR signaling activator with anti-breast cancer properties in vitro and in vivo.

Breast cancer is one of the main causes of malignancy-related deaths globally and has a significant impact on women's quality of life. Despite significant therapeutic advances, there is a medical need for targeted therapies in breast cancer. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor mediates responses to environment stimuli, is emerging as a unique pleiotropic target.

Network Pharmacology- and Molecular Docking-Based Identification of Potential Phytocompounds from in the Treatment of Inflammation.

The methanolic extract of stem was examined for anti-inflammatory activities following network pharmacology analysis and molecular docking study. Based on gas chromatography-mass spectrometry (GC-MS) analysis, 49 compounds were identified from the methanolic extract of stem. A network pharmacology analysis was conducted against the identified compounds, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology analysis of biological processes and molecular functions were performed.

Activation of aryl hydrocarbon receptor signaling by gallic acid suppresses progression of human breast cancer in vitro and in vivo.

Background: Despite the significant advances in diagnosis and treatment, breast cancer remains the most common malignancy and the second cause of death in women. Increasingly, preclinical evidence has suggested aryl hydrocarbon receptor (Ahr), a ligand activated transcription factor, a promising therapeutic target in breast cancer.

Purpose: This study aims at screening a number of phenolic compounds to identify an Ahr ligand with suppressive effects on human breast cancer.

Interplay of Halogen and Hydrogen Bonding through Co-Crystallization in Pharmacologically Active Dihydropyrimidines: Insights from Crystal Structure and Energy Framework.

A solvent-assisted grinding method has been used to prepare co-crystals in substituted dihydropyrimidines (DHPM) that constitutes pharmacologically active compounds. These were characterized using FT-IR, PXRD, and single-crystal X-ray diffraction. In order to explore the possibility of formation of halogen (XB) and hydrogen bonding (HB) synthons in the solid state, co-crystallization attempts of differently substituted DHPM molecules, containing nitro, hydoxy, and chloro substituents, with different co-formers, such as 1,4-diiodo tetrafluorobenzene (1,4 DITFB) and 3-nitrobenzoic acid (3 NBA) were performed.

Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives.

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (-) were carried out and evaluated for COX-2 enzyme inhibition.

Computational analysis of non-competitive antagonist arylguanidine-α7 nAChR complexes.

meta-Chlorophenylguanidine (1) is a non-competitive α7 nicotinic acetylcholine receptor (nAChR) antagonist. Here we examined the hydrogen bond donor role of the anilinic N-H on the inhibitory effect of 1 by preparing its N-CH counterpart 2. Analog 2 was found to be at least as potent as 1 as a non-competitive α7 nAChR antagonist in a patch-clamp assay.

NH- and N-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure-Activity Relationship Studies.

We previously reported that -(3-chlorophenyl)guanidine () represents a novel α7 nicotinic ACh (nACh) receptor antagonist chemotype. In the present study, a small series of compounds was synthesized with the intent to investigate the structure-activity relationship (SAR). Preliminary data suggested that the N-methyl analog of , , was several times more potent.

Crystallography, in Silico Studies, and In Vitro Antifungal Studies of 2,4,5 Trisubstituted 1,2,3-Triazole Analogues.

A series of 2,4,5 trisubstituted-1,2,3-triazole analogues have been screened for their antifungal activity against five fungal strains, , , , , and , via a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) microdilution assay. Compounds GKV10, GKV11, and GKV15 emerged as promising antifungal agents against all the fungal strains used in the current study. One of the highly active antifungal compounds, GKV10, was selected for a single-crystal X-ray diffraction analysis to unequivocally establish its molecular structure, conformation, and to understand the presence of different intermolecular interactions in its crystal lattice.

In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against .

Background And Purpose: Tuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease.

Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector , In Silico ADMET Prediction and Molecular Target Investigation.

Malaria, affecting all continents, remains one of the life-threatening diseases introduced by parasites that are transmitted to humans through the bites of infected mosquitoes. Although insecticides are currently used to reduce malaria transmission, their safety concern for living systems, as well as the environment, is a growing problem. Therefore, the discovery of novel, less toxic, and environmentally safe molecules to effectively combat the control of these vectors is in high demand.

Antidiabetic Activity of Dihydropyrimidine Scaffolds and Structural Insight by Single Crystal X-ray Studies.

Background: This research project is designed to identify the anti-diabetic effects of the newly synthesized compounds to conclude the perspective of consuming one or more of these new synthetic compounds for diabetes management.

Introduction: A series of dihydropyrimidine (DHPM) derivative bearing electron releasing and electron-withdrawing substituent's on phenyl ring (a-j) were synthesized and screened for antihyperglycemic( anti-diabetic) activity on streptozotocin (STZ) induced diabetic rat model. The newly synthesized compounds were characterized by using FT-IR, melting point, 1H and 13C NMR analysis.

Synthesis, cytotoxic evaluation, and molecular docking studies of novel quinazoline derivatives with benzenesulfonamide and anilide tails: Dual inhibitors of EGFR/HER2.

We synthesized a new series of 2-[(3-(4-sulfamoylphenethyl)-4(3H)-quinazolinon-2-yl)thio]anilide derivatives (2-16) and evaluated their cytotoxic activity against breast adenocarcinoma (MCF-7), colorectal adenocarcinoma (HT-29), and acute myeloid leukemia (HL-60 and K562) cells. To reveal their selectivity toward cancer cells, the compounds were also tested against the human fibroblast cell line, MRC-5. Compounds 1-5 exhibited potent cytotoxic activity against the tested cell lines with IC values of 0.

Anti-Tubercular Activity of Substituted 7-Methyl and 7-Formylindolizines and In Silico Study for Prospective Molecular Target Identification.

Novel series of diversely substituted indolizines were designed, synthesized, and evaluated for their in vitro anti-mycobacterial activity against H37Rv and multi-drug-resistant (MDR) strains of (MTB). Many compounds exhibited significant inhibitory activity against MTB H37Rv strains. Indolizines 2d, 2e, and 4 were also found to be active against MTB clinical isolates with multi-resistance to rifampicin and isoniazid.

Novel Series of Methyl 3-(Substituted Benzoyl)-7-Substituted-2-Phenylindolizine-1-Carboxylates as Promising Anti-Inflammatory Agents: Molecular Modeling Studies.

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity.

Design, synthesis, and structural elucidation of novel NmeNANAS inhibitors for the treatment of meningococcal infection.

Neisseria meningitidis is the primary cause of bacterial meningitis in many parts of the world, with considerable mortality rates among neonates and adults. In Saudi Arabia, serious outbreaks of N. meningitidis affecting several hundreds of pilgrims attending Hajj in Makkah were recorded in the 2000-2001 season.

Activation of aryl hydrocarbon receptor signaling by a novel agonist ameliorates autoimmune encephalomyelitis.

Background: Multiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, is a promising treatment target for MS. Thus, the current study aimed to identify a novel Ahr ligand with anti-inflammatory potential in experimental autoimmune encephalomyelitis (EAE).

"Methylene Bridge" to 5-HT Receptor Antagonists: Conformationally Constrained Phenylguanidines.

Arylguanidines, depending upon their aromatic substitution pattern, display varying actions at 5-HT receptors (e.g., partial agonist, agonist, superagonist).

Synthesis and Structural Elucidation of Novel Benzothiazole Derivatives as Anti-tubercular Agents: In-silico Screening for Possible Target Identification.

Background: Benzothiazole derivatives are known for anti-TB properties. Based on the known anti-TB benzothiazole pharmacophore, in the present study, we described the synthesis, structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives (BNTZ 1-7 and BNTZ 8-13).

Objective: The study aims to carry out the development of benzothiazole based anti-TB compounds.

Molecular modeling studies and anti-TB activity of trisubstituted indolizine analogues; molecular docking and dynamic inputs.

A series of trisubstituted indolizine analogues has been designed as a result of a fragment-based approach to target the inhibition of mycobacterial enoyl-acyl carrier protein reductase. Anti-tuberculosis (TB) screening of the characterized compounds by a resazurin microplate assay method revealed that ethyl group at second position of indolizine nucleus exhibited activity against susceptible and multidrug-resistant strains of Mycobacterium tuberculosis at concentration of 5.5 and 11.

Design, synthesis, and characterization of (1-(4-aryl)- 1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against Mycobacterium tuberculosis.

The novel (1-(4-aryl)-1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives were synthesized by the click reaction of the dihydropyrimidinones, bearing a terminal alkynyl group, with various substituted aryl azides at room temperature using a catalytic amount of Cu(OAc)2 and sodium ascorbate in a 1:2 ratio of acetone and water as a solvent. The newly synthesized compounds were characterized by a number of spectroscopic techniques, such as infrared, liquid chromatography-mass spectrometry, (1)H, and (13)C nuclear magnetic resonance along with single crystal X-ray diffraction. The current procedure for the synthesis of 1,2,3-triazole hybrids with dihydropyrimidinones is appropriate for the synthesis of a library of analogs 7a-l and the method accessible here is operationally simple and has excellent yields.