Medicinal Chemistry最新文献

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.

Introduction: Histamine Type I Receptor Antagonists (H1 blockers) are widely used to mitigate histamine-induced inflammation, particularly in allergic reactions. Histamine, a biogenic amine found in endothelial cells, vascular smooth muscle, bronchial smooth muscle, and the hypothalamus, is a key player in these responses. H1 blockers are essential in cough syrups and flu medications and are divided into two generations: first-generation H1 blockers, which are sedating and have numerous side effects, and second-generation blockers, which are non-sedating and generally less toxic but may still exhibit cross-reactivity with other receptors.

Method: In this study, a comprehensive database of compounds was utilized alongside fexofenadine as a benchmark to discover compounds with potentially superior efficacy and reduced side effect profiles. In particular, multidimensional K-means clustering, a machine-learning technique, was applied to identify compounds with chemical structures similar to fexofenadine.

Result: Utilizing computational prediction of pharmacokinetic profile and molecular docking experiments, the action of these drugs on the H1 receptor was assessed. Furthermore, the crossreactivity of antihistamines was investigated by conducting a structure-based pharmacophore feature analysis of the docked poses of highly toxic antihistamines with various receptors.

Conclusion: By identifying and proposing the removal of common toxic features, we aim to facilitate the development of antihistamines with fewer adverse effects.

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.

Azaaurones are formed by the replacement of intra-cyclic oxygen of the central core of a five-membered furan ring or any other carbon of aurones by a nitrogen atom. However, 1- azaaurone obtained by the replacement of intra-cyclic oxygen is the most prominent and desirable. They are the bioactive compounds acting as potential anti-inflammatory, anticancer, antibacterial, and antiviral agents. They comprise relatively less explored, pharmacologically active compounds exhibiting diverse biological activities that can act as potential lead compounds in the context of drug development. This review represents a comprehensive and updated overview of the synthetic protocols and biological activities of 1-azaaurones and their derivatives, enabling the readers to know about the vast medicinal potential of azaaurones and their derivatives in different areas and prompt the medicinal chemists to emphasize their further exploration. Furthermore, this review also covers some important Structure-Activity Relationships (SAR), highlighting the most potential compounds in each series, providing pivotal scope for further improvisation.

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.

Cyclin-Dependent Kinase (CDK) 12 is a member of the 20-membered CDK family (CDK1-20) and plays a vital role in regulating gene transcription, mRNA splicing, translation, cell cycle, and repair of DNA damage. CDK12 is an emerging therapeutic target due to its role in regulating the transcription of DNA Damage Response (DDR) genes in Cyclin-Dependent Kinase (CDK). However, the development of selective small molecules targeting CDK12 has been challenging due to the high degree of homology between kinase domains of CDK12 and other transcriptional CDKs, most notably CDK13. So far, no CDK12 inhibitors approved by the US FDA have been found, and more novel CDK12 inhibitors have been reported for the treatment of prostate cancer, breast cancer, ovarian cancer, lung adenocarcinoma, stomach cancer, cervical cancer, etc. This review has attempted to summarize the structural characteristics and biological activities of various novel CDK12 inhibitors reported since 2020. Meanwhile, we collated and analyzed the reported CDK12 inhibitors from the perspective of structure, summarized the current clinical application potential of CDK12 inhibitors, and further analyzed their current challenges and future development trends.

Background: Owing to their extensive utilization as pesticides, heterocycles assume a fundamental role in the management of vector-borne diseases. Despite the presence of numerous heterocyclic compounds in commercial insecticides and larvicides, resistance to pesticides still demands novel strategies to current pest control methods. Considering these facts, this review aims to survey the synthesis and SAR of heterocyclic molecules with larvicidal activity against Aedes aegypti Linn.

Methods: Comprehensive searches across the major databases were conducted to identify heterocyclic compounds exhibiting larvicidal efficacy against Ae. aegypti with the goal to unveil the main characteristics that are essential for exhibiting larvicidal activity.

Results: Active compounds display LC50 values varying from 0.36 to 2907 μM. Fifteen heterocyclic compounds displayed larvicidal activities below 20 μM. Five-membered ring molecules containing nitrogen and oxygen have displayed larvicidal activity according to the position of heteroatoms in the ring. Molecules bearing 1,2,4-oxadiazole and 1,2-oxazole moieties have been shown to be more active than 1,3,4-oxadiazole derivatives. Compounds possessing the indole scaffold have proven to be more potent than isatin and pyrimidine derivatives. Structural characteristics other than a heterocyclic moiety, such as the presence of halogens and less ionized and polar molecules, may also play a role in determining the final larvicidal activity.

Conclusion: The rationale behind this review is to stimulate the discovery of innovative heterocyclic larvicides. Thus, it is important to continue synthesizing new scaffolds to comprehensively elucidate the structure-activity relationship for each heterocyclic moiety outlined in this investigation.

The escalating prevalence of lifestyle and microbial diseases poses a significant threat to human well-being, necessitating the discovery and development of novel drugs with distinct modes of action. Addressing this challenge involves employing innovative strategies, and one current approach involves utilizing heterocyclic compounds to synthesize hybrid molecules. These hybrids have resulted from the fusion of two or more bioactive heterocyclic moieties into a single molecule. The focus of this review revolves around the strategic incorporation of heterocycles, particularly thiazole derivatives. Thiazole derivatives, due to their unique structural features, are explored in depth within this review paper. The paper comprehensively outlines diverse hybridization strategies of thiazole derivatives, highlighting their vibrant biological activities mainly in the last decade, 2014-2024. By presenting an extensive overview, the review aims to provide valuable insights into the potential of thiazole derivatives as promising candidates for drug development. The insights garnered from this paper are expected to offer valuable guidance for future drug design endeavors, providing a foundation for developing novel and effective drugs to combat lifestyle diseases and microbial resistance.

Background: Neurodegenerative diseases are a group of disorders characterized by progressive neuronal degeneration and death, of which Alzheimer's disease and Parkinson's disease are the most common. These diseases are closely associated with increased expression of monoamine oxidase B (MAO-B), an important enzyme that regulates neurotransmitter concentration, and its overactivity leads to oxidative stress and neurotoxicity, accelerating the progression of neurodegenerative diseases. Therefore, the development of effective MAO-B inhibitors is important for the treatment of neurodegenerative diseases.

Objective: This study aims to improve the prediction of the efficacy of novel 6-hydroxybenzothiazole- 2-carboxamide compounds in inhibiting MAO-B by improving the quantitative constitutive effect relationship (QSAR) modeling and to provide a theoretical basis for the discovery of novel neuroprotective drugs.

Methods: The study first optimized the structures of 36 compounds using the heuristic method (HM) in CODESSA software to construct linear QSAR models. Subsequently, key descriptors were screened by using the gene expression programming (GEP) technique to generate nonlinear QSAR models and validate them.

Results: The R², F-value, and R²cv of the linear model were 0.5724, 10.3752, and 0.4557, respectively, whereas the nonlinear model constructed by the GEP algorithm showed higher prediction accuracies by achieving R² values of 0.89 and 0.82, and mean squared errors (MSE) of 0.0799 and 0.1215 for the training and test sets, respectively. In addition, molecular docking experiments confirmed that the novel compound 31 was tightly bound to the MAO-B active site with significant inhibitory activity.

Conclusion: In this study, we successfully improved the prediction ability of the efficacy of novel 6-hydroxybenzothiazole-2-carboxamide compounds to inhibit MAO-B by improving the QSAR model. This not only provides new drug candidates for the treatment of neurodegenerative diseases, but also provides important theoretical guidance for subsequent drug design and development, which can help accelerate the process of new drug discovery and reduce the disease burden of patients.