Synthesis and evaluation of analgesic, anti-asthmatic activity of (E)-1-(8-hydroxyquinolin-7-yl)-3-phenylprop-2-en-1 ones

Abstract Seventeen (E)-1-(8-hydroxyquinolin-7-yl)-3-phenylprop-2-en-1 one derivatives were synthesized via aldol condensation of substituted benzaldehydes with quinoline chalcones starting from 8-hydroxy quinoline. Molecular docking studies were performed on COX-2 protein for analgesic activity and PDE 4 enzyme for anti-asthmatic activity. Docking studies for analgesic activity reveal that the compounds 2 , 4 , 12 , 14 , and 15 showed significant interaction in terms of hydrogen bonding, hydrophobic attachment and van der Waal interaction with COX-2. The docking studies and pharmacological screening indicate that substitution of hydroxyl and conjugated ketone groups on the aldehyde ring and the quinoline ring accelerates analgesia with better binding to active site. Eddy's hot plate method was used to evaluate analgesic activity of the synthesized compounds. Compounds showed a substantial increase in reaction time when compared with standard pentazocin. Compounds 2 , 4 , 7 , 9 and 13 showed significant binding interactions with PDE 4 enzyme and hence were selected for evaluation of anti-asthmatic activity using the goat tracheal chain method. Studies reveal that substitution of the methoxy group at 4th & 5th positions for compounds 2 , 4 & 7 leads to significant percentage inhibition of histamine induced contraction. The synthesized compounds are thus found to be potent as analgesic and anti-asthmatic agents

Magnetic hydrogel (MagGel): An evolutionary pedestal for anticancer therapy

Recent advancement in biomaterials have led to the development of magnetic hydrogel as promising tool for anticancer therapy. Magnetic hydrogels improve injectability over bare nanoparticles by controlling particle dispersion and reducing aggregation, ensuring uniform delivery and minimizing clogging, thereby enhancing anticancer therapy effectiveness and safety. This review explores the fundamental crosslinking methodologies and chemical strategies for the formation of hydrogels, transitioning into detailed discussions on the synthesis of magnetic hydrogels, emphasizing their unique properties essential for biomedical applications. Key properties such as injectability, shear thinning, biocompatibility, porosity, mechanical properties, and biodegradability underpinning the efficacy of magnetic hydrogels in biomedical applications are discussed. Furthermore, the review highlights the diverse applications of magnetic hydrogels in the biomedical field, including hyperthermia, MRI-guided therapy, targeted drug delivery, and tissue engineering. These properties and applications demonstrate the potential of magnetic hydrogels to revolutionize cancer treatment and other medical therapies, offering a multifunctional platform that can address various biomedical challenges with enhanced precision and effectiveness. Finally, future research trends and applications of magnetic hydrogels are also recommended and examined.</p

Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT2C Agonists

Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT2C agonists. To improve selectivity for 5-HT2C over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds 10a and 10f as potent 5-HT2C agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine 10a showed a highly agonistic effect on the 5-HT2C receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine 10a could be considered a viable lead compound as a 5-HT2C selective agonist

Discovery of N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide: a novel, selective, and competitive indole-based lead inhibitor for human monoamine oxidase B

Herein, two new series of N-substituted indole-based analogues were rationally designed, synthesized via microwave heating technology, and evaluated as noteworthy MAO-B potential inhibitors. Compared to the reported indazole-based hits VI and VII, compounds 4b and 4e exhibited higher inhibitory activities over MAO-B with IC50 values of 1.65 and 0.78 µM, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), both 4b and 4e also showed better selectivity indices (SI > 60 and 120, respectively). A further kinetic evaluation of the most potent derivative (4e) displayed a competitive mode of inhibition (inhibition constant (Ki)/MAO-B = 94.52 nM). Reasonable explanations of the elicited biological activities were presented via SAR study and molecular docking simulation. Accordingly, the remarkable MAO-B inhibitory activity of 4e (N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide), with its selectivity and competitive inhibition, advocates its potential role as a promising lead worthy of further optimization

Endosomal escape in magnetic nanostructures: Recent advances and future perspectives

Several evolving therapies depend on the delivery of therapeutic cargo into the cytoplasm. Engineered magnetic nanoparticles (MNPs) have played a pivotal role in advancing and modernizing cancer theranostics, vaccination and gene therapies. The main advantages of MNP-based delivery approaches are due to their potential to decrease the side effects by targeting specific cell types, shielding delicate therapeutics from early degradation, increasing the solubility of hard-to-deliver drugs and long-sustained and precise release of these drugs. Like other nanoparticles (NPs), MNPs enter cells by endocytosis and are frequently stuck inside endocytic vesicles, which mature into early and late endosomes and accumulate in the lysosome. Endocytosed MNPs are ultimately degraded in lysosomes or recycled towards the cell membrane. Thereby, they must escape endocytic vesicles on a priority basis. Endosomal escape is highly important for the effectiveness of nanoparticle-based treatments. This review is concerned with the use of magnetic nanoparticles (MNPs) as functional nano-objects to enhance the therapeutic effects by disrupting or rupturing the endocytic vesicles in terms of endosomal escape. The current strategies and future challenges concerning an efficient endosomal escape of MNPs are discussed in this review

Synthesis and evaluation of an orally available &quot;Y&quot;-shaped biaryl peroxisome proliferator-activated receptor delta agonist

In this study, we designed and synthesized several novel &quot;Y&quot;-shaped biaryl PPARS agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50 = 0.7 nM) shows much more potent activity than S isomer (EC50 = 6.1 nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPAR delta agonist 3a is a viable drug candidate for the treatment of various PPARS-related disorders.OAIID:RECH_ACHV_DSTSH_NO:T201810706RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A000128CITE_RATE:2.442DEPT_NM:지구환경과학부EMAIL:[email protected]_YN:YN

Endosomal escape in magnetic nanostructures: recent advances and future perspectives

Several evolving therapies depend on the delivery of therapeutic cargo into the cytoplasm. Engineered magnetic nanoparticles (MNPs) have played a pivotal role in advancing and modernizing cancer theranostics, vaccination and gene therapies. The main advantages of MNP-based delivery approaches are due to their potential to decrease the side effects by targeting specific cell types, shielding delicate therapeutics from early degradation, increasing the solubility of hard-to-deliver drugs and long-sustained and precise release of these drugs. Like other nanoparticles (NPs), MNPs enter cells by endocytosis and are frequently stuck inside endocytic vesicles, which mature into early and late endosomes and accumulate in the lysosome. Endocytosed MNPs are ultimately degraded in lysosomes or recycled towards the cell membrane. Thereby, they must escape endocytic vesicles on a priority basis. Endosomal escape is highly important for the effectiveness of nanoparticle-based treatments. This review is concerned with the use of magnetic nanoparticles (MNPs) as functional nano-objects to enhance the therapeutic effects by disrupting or rupturing the endocytic vesicles in terms of endosomal escape. The current strategies and future challenges concerning an efficient endosomal escape of MNPs are discussed in this review.</p

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual.

Amyotrophic lateral sclerosis (ALS) is a severe disease causing motor neuron death, but a complete cure has not been developed and related genes have not been defined in more than 80% of cases. Here we compared whole genome sequencing results from a male ALS patient and his healthy parents to identify relevant variants, and chose one variant in the X-linked ATP7A gene, M1311V, as a strong disease-linked candidate after profound examination. Although this variant is not rare in the Ashkenazi Jewish population according to results in the genome aggregation database (gnomAD), CRISPR-mediated gene correction of this mutation in patient-derived and re-differentiated motor neurons drastically rescued neuronal activities and functions. These results suggest that the ATP7A M1311V mutation has a potential responsibility for ALS in this patient and might be a potential therapeutic target, revealed here by a personalized medicine strategy

Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington\u27s disease mouse model.

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington\u27s disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined in silico and in vitro cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD