Medicinal Chemistry最新文献

Indazole-based compounds have recently developed and physiologically evaluated as diverse agents for antibacterial, anticancer, anti-inflammatory, anti-obesity, and neurological therapies. This review highlights these advancements. Through molecular docking and experimental tests, scientists have created distinct indazole analogs that exhibit significant inhibitory effects on various biological targets, including 1,2,3-triazolyl-indazoles, carbothioamides, and carboxamides. Key compounds have demonstrated strong bactericidal and antifungal properties against microbes such as S. epidermidis, P. aeruginosa, E. coli, and C. albicans; their effectiveness was enhanced by halogenated and electron-withdrawing substituents. In models including positive HER2 breast cancer and hepatocellular tumors, indazole derivatives have shown efficacy against targets such as CDK2, EGFR, c-Met, HSP90, and VEGFR2 in oncology, resulting in successful anticancer responses. The pharmacokinetics, solubility, and specificity of these compounds have been further improved through structural alterations, such as piperazine ring modifications and C-terminal changes. Additionally, the LRRK2 antagonist MLi-2 demonstrated remarkable efficacy in treating neurodegenerative diseases, while indazole-5-carboxamides exhibited a strong affinity for monoamine oxidases, potentially offering new therapeutic options for Parkinson's disease. Inhibition of COX-2 and FGFR resulted in anti-inflammatory effects, with minimal off-target damage observed in vivo. Collectively, our findings underscore the therapeutic versatility of indazole frameworks across various disease pathways, suggesting their potential for developing innovative treatments for cancer, infections, metabolic disorders, and neurological conditions.

Pyrimidine derivatives are a class of chemically & biologically active heterocyclic compounds promising for developing anti-tubercular, anti-viral, anti-malarial, anti-inflammatory, and enzyme-inhibiting drugs. To cure TB, scientists were driven to establish novel pyrimidine derivatives. The main objective of the current review is to identify and develop new pyrimidine moietycontaining derivatives that have been assessed for their structure-activity relationship (SAR). The emergence and widespread spread of several drug-resistant MTB infections, which renders firstline anti-TB medications more ineffective. It is crucial to develop new anti-TB drugs that are extremely effective against both drug-sensitive and drug-resistant TB. The development of pyrimidine therapeutics methods will thus benefit from the current review. Three medications-GSK-286, TBA- 7371, and SPR-720 are now undergoing clinical testing. This study aims to emphasize the structural variety of anti-tuberculosis pyrimidine-containing compounds by providing an overview of current developments in drug discovery investigations.

Objective: In the pursuit of identifying divergent scaffolds for potential anticancer and anti-mycobacterial agents, a novel series of Schiff-based threaded 1,2,3-triazoles was designed and synthesized.

Methods: In this study, novel Schiff-based threaded 1,2,3-triazoles have been meticulously crafted and synthesized. Chemical structures of the synthesized molecules were confirmed by 1H NMR, 13C NMR and Mass spectra. Synthetic analogs were further evaluated for their antiproliferative, antitubercular and antimicrobial potentials by in vitro assays.

Results: The in vitro anti-tumor (anti-proliferative) evaluation on HT29 cancer cells revealed that compounds 8b and 8h exhibited remarkable inhibitory activity with IC50 values of 25±0.8 and 24±0.9 μM. In the context of anti-mycobacterial analysis, compound 8c demonstrated promising activity (6.25 μM) against Mycobacterium tuberculosis H37Rv. Moreover, compounds 8d and 8e displayed equipotent antimicrobial potential (3.12 μM) comparable to Ciprofloxacin against both Staphylococcus aureus and Escherichia coli. Molecular docking studies unveiled that 8c exhibited robust binding within the active pocket of carbonic anhydrase XII (docking energy -8.4 kcal/mol) and demonstrated a promising docking profile with β-ketoacyl ACP synthase I (docking energy - 9.5 kcal/mol) in the enzyme's binding pocket.

Conclusion: Structure-activity relationship (SAR) analysis identified three pivotal pharmacophores; 1,2,3-triazole, aromatic ring system (substituted with halogens and -NO2), and imine functionalities as crucial for the development of dual inhibitors targeting cancer and tuberculosis, showcasing an outstanding in silico ADMET profile. Therefore, these compounds merit consideration as noteworthy pharmacological lead molecules in the realm of cancer and tuberculosis drug discovery and development.

Background: PARP1 (poly ADP-ribose polymerase 1, also known as ADPRT1) plays a significant role in DNA repair and has become an attractive target for treating PARP1-related diseases, such as cancer.

Objective: This study aimed to discover inhibitors targeting PARP1 from the phytochemicals of Huangbai (Phellodendron chinense Schneid.), Baixianpi (Dictamnus dasycarpus Turcz.), and Shechuangzi (Cnidium monnieri (L.) Spreng.).

Methods: The chemical compositions of Huangbai, Baixianpi, and Shechuangzi were extracted from the HERB database. Next, a combination of molecular docking and PARP1 enzyme assay was used to identify PARP1 inhibitors from these chemical components. Finally, molecular dynamics simulation and binding free energy calculation were used to explore the detailed interaction mode of these inhibitors with PARP1.

Results: A total of 507 chemical constituents of Huangbai, Baixianpi, and Shechuangzi were collected from the HERB database. Four potential PARP1 inhibitors were screened based on molecular docking and PARP1 enzyme assay. Demethyleneberberine exhibited strong PARP1 inhibitory activity with an IC50 value of 2.0 ± 0.8 μM. The IC50 values of the inhibitory activities of 8-hydroxy dictanmnine, meranzin hydrate, and osthol on PARP1 ranged from 44 μM to 76 μM. Molecular dynamics simulation and binding free energy calculation suggested that the nonpolar interaction energies of HIS862, GLY863, TYR889, TYR896, PHE897, and TYR907 played a primary role in the binding of inhibitors to PARP1.

Conclusion: Integrating molecular simulation and bioactivity testing was found to be an effective approach for the rapid discovery of targeted PARP1 inhibitors. Demethyleneberberine demonstrated strong PRAP1 inhibitory activity and has a good prospect for development.

Aim: A simple and efficient synthesis of 14 new (9a-9n) N-phenacyl-2-pyridones with good yields (up to 75%), is reported. The synthesized derivatives were screened for their in vitro radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), their in vitro antimicrobial potential was tested against human pathogenic bacterial strains, including Bacillus cereus, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, as well as the fungal strain Candida albicans.

Method: All compounds displayed modest antioxidant activity, with compound 9b being the most potent in the DPPH radical scavenging assay. Most of the synthesized compounds exhibited good to excellent antimicrobial activity, however, the compounds (9d, and 9b) showed maximum inhibition zone diameters of 18.75, and 18.25mm respectively, demonstrating better antimicrobial potential than the standard drug streptomycin against Staphylococcus aureus.

Result: However, the compound 9f was found most effective against Pseudomonas aeruginosa with a 23.25 mm zone of inhibition against a 17.50 mm zone of inhibition of the standard, streptomycin. Molecular docking of the compounds 9d and 9f with tyrosyl-tRNA synthetase revealed good binding with the target.

Conclusion: The electron-withdrawing substituents on the aryl ring of synthesized N-phenacyl-2- pyridones improved the antioxidant activity, however, for Gram-positive bacteria, less lipophilic or more hydrophilic substituents, such as halogens, displayed better antimicrobial activity. Similarly, it was the more lipophilic substitutions on the aryl ring that improved the antimicrobial activity against Gram-negative bacteria.

Background: Myrica esculenta (Myricaceae) are common in the Indian Himalayas. Traditional medicine uses it to treat chronic bronchitis, inflammation, stomach ulcers, anaemia, diarrhoea, asthma, and ear, throat, and nose disorders. Its varied medicinal benefits are recognised in the ayurvedic pharmacopoeia.

Aim: Isolation of Bioactive Compounds from M. esculenta: Assessment of Antioxidant Activity and Molecular Docking Studies Targeting the H+K+-ATPase enzyme and H2 Receptor Material and Methods: The fruit of the Myrica esculenta plant was extracted. The total phenolic and total flavonoid content of the extract were determined. Following column chromatography, two phytoconstituents were identified by mass spectroscopy, FTIR, and NMR. The antioxidant activity of phytoconstituents was evaluated using the DPPH Scavenging Assay, Reactive Nitrogen Oxide Scavenging Assay, and Hydroxyl Free Radical Scavenging Assay. Then, molecular docking studies were performed against the H+K+-ATPase enzyme and H2 Receptor.

Results: The research successfully extracted methanolic extract from M. esculenta by maceration, which yielded rich in flavonoids and phenolic content and isolated compounds using column chromatography, which was further characterized to be myricetin and catechin using Mass spectroscopy, FTIR, and NMR. The further evaluation of the antioxidant activity of compounds demonstrated significant activity with IC50 value indicating strong free radical scavenging activity. Molecular docking studies were performed against the H+K+-ATPase enzyme and H2 Receptor, revealing that both the compounds exhibit high binding affinity and favorable interactions with key sites.

Conclusion: The findings suggest that the isolated compounds myricetin and catechin possess potential antioxidant activity and could be a potential therapeutic target for the H+K+-ATPase enzyme and H2 Receptor.

Pyridine and its derivatives are six-membered aromatic rings containing nitrogen, which are abundant in nature and indispensable in studying heterocyclic chemistry. They constitute significant chemical substances with numerous applications. The application of pyridine derivatives by incorporating metals in modern medicine is growing in relevance. Due to their convenient parallelization and various testing capabilities in the chemical domain, pyridine derivatives have attracted increased interest in the treatment of various disease states. This review aims to systematically evaluate and highlight the recent advancements in the synthesis (conventional, synthetic, and green approach) and biological activities of metal-based pyridine derivatives, including antioxidant, antimicrobial, and antitumor activities, while identifying promising candidates for further drug development. By consolidating all this knowledge underlying their biological effects, this review aims to pave the way for future research endeavors and encourage the exploration of pyridine derivatives as viable therapeutic agents across a diverse array of medical applications.

Background: Diabetes mellitus and obesity are two of the most frequent health conditions in the world, prompting medical researchers to seek novel effective treatments. According to World Health Organization (WHO) regulations and several research studies, diabetes is regarded as a significant and leading health concern worldwide. The search for efficient and safe antidiabetic drugs has led to the study of pyridine derivatives, a family of molecules with a wide range of pharmacological characteristics. Pyridines are important heterocyclic chemicals renowned for their various pharmacological properties.

Methods: Materials were compiled using the three databases of ScienceDirect, PubMed, and Google Scholar. For this study, only English-language publications have been evaluated based on their titles, abstracts, and full texts using keywords like diabetes, pyridine Derivatives, α- glucosidase inhibitors, and α-amylase inhibitors.

Results: Pyridine and its derivatives have received a lot of attention due to their wide range of potential uses in medicinal chemistry and pharmacology. Structural alterations and optimization efforts have resulted in higher effectiveness, selectivity, and safety characteristics. These discoveries highlight the importance of pyridine analogues as a novel class of therapeutic agents for diabetes management.

Conclusion: The review highlights the significance of pyridine analogues in the development of antidiabetic treatments, opening new avenues for developing drugs and clinical use. The ongoing advancements in the discovery of pyridine derivatives underscore their potential as prospective agents in diabetic treatments.

Introduction: Heterocyclic derivatives, particularly those containing heteroatoms such as oxygen and nitrogen, represent a significant portion of currently marketed drugs. Among these, the aromatic heterocycle 1,3,4-oxadiazole, characterized by an N=C=O-linkage, stands out due to its remarkable biological activities. These activities include anti-inflammatory, anti-cancer, antioxidant, anti-tubercular, antiviral, anti-diabetic, and antibacterial effects. Notably, several commercially available medications, such as tiodazosin, raltegravir, zibotentan, and nesapidil, incorporate this structural motif.

Methods: This review compiles and analyzes existing synthetic methods for preparing 1,3,4- oxadiazole and its derivatives. By examining various synthetic routes and methodologies, the review provides a detailed overview of the strategies employed to generate these biologically active compounds.

Results: The review highlights the potential of 1,3,4-oxadiazole derivatives in addressing the toxicity, side effects, and drug resistance commonly associated with existing anticancer therapies. By combining the 1,3,4-oxadiazole moiety with other heteroatoms, novel hybrid derivatives have been synthesized, demonstrating enhanced pharmacological activities across various therapeutic areas.

Conclusion: This comprehensive review offers valuable insights into the synthesis and pharmacological applications of 1,3,4-oxadiazoles. It serves as a crucial resource for researchers exploring the development of new therapeutic compounds, with the ultimate goal of improving public health. The review builds on existing literature from the last two decades to present an exhaustive examination of the potential of 1,3,4-oxadiazole derivatives in drug development.

Background: Dopamine (1) is a commonly used vasopressor, primarily employed to treat various types of shock, congestive heart failure, and acute renal failure. Dopamine dimer (2) is an impurity generated during the production process of dopamine raw materials or the metabolism of dopamine drugs themselves.

Methods: This article presents an effective method for synthesizing dopamine dimer through the condensation of methyl 3,4-dimethoxyphenyl acetate (4) and 3,4-dimethoxyphenylethyl amine (5), followed by reduction and demethylation.

Results: The product was synthesized from easily accessible raw materials, achieving a total yield of 48% over five steps.

Conclusion: This synthesis method is simple and beneficial for pharmaceutical companies to adopt and implement.