Medicinal Chemistry最新文献

The five-membered oxazole motif heterocyclic aromatic ring has been gaining considerable attention due to its bioisosterism property and unusually wide range of desired biological properties. Thus, it is a perfect pre-built platform for the discovery of new scaffold development in medicinal chemistry. In recent years, the potential of oxazoles has garnered significant attention from medicinal chemists, resulting in the development of several synthetic and plant-based drugs currently in the market. Interest in the biological applications of oxazoles has notably intensified over the past fifteen years. This overview aims to provide a comprehensive, systematic summary of recent advancements in the synthetic chemistry of oxazole-based compounds, highlighting significant progress in their biological applications during this period as well as outlining prospects for further development. In summary, we overview literature in synthetic chemistry and explore structure- activity relationships and mechanisms of action with medicinal applications for the development of oxazole derivatives that hold promise for discovering new and effective drug candidates.

Background: The rise in the frequency of liver cancer all over the world makes it a prominent area of research in the discovery of new drugs or repurposing of existing drugs.

Methods: This article describes the pharmacophore-based structure-activity relationship (3DQSAR) on the secondary metabolites of Alhagi maurorum to inhibit human liver cancer cell lines Hepatocellular carcinoma (HCC) and hepatoma G2 (HepG2) which represents the molecular level understanding for isolated phytochemicals of Alhagi maurorum. The definite features, such as hydrophobic regions, average shape, and active compounds' electrostatic patterns, were mapped to screen phytochemicals. The 3D-QSAR model generates pharmacophore-based descriptors and alignment of active compounds. Further, docking studies were performed on the active compounds to check out their binding affinity with the active site of the target proteins. It was further validated by applying molecular simulations, and the results were found to be accurate. The geometrical optimization and energy gap of the hit compound were calculated by the density functional theory (DFT). Then, ADMET was performed on this hit compound for drug-like features and toxicity.

Result: Out of 59 compounds, eight ligands were found active after the 3D-QSAR study. After that, molecular docking was performed on the active compounds F72, F52, F54, F29, F37, F38, F25, and F29, which were recognized as potential targets, and the docking results showed that compound F52 (also an FDA-approved drug) was the best hit. F52 was found to be the best hit against liver cancer cell lines HCC and HepG2.

Conclusion: This study would be helpful for early drug discovery optimization and lead identification.

Background: Glioblastoma Multiforme (GBM), a highly aggressive and prevalent brain cancer with a higher incidence in males, has limited treatment success due to drug resistance, inadequate targeting and penetration of cancer cells, and an incomplete understanding of its molecular pathways. GBM is a highly aggressive brain cancer with limited treatment options. This study investigates the anticancer potential of synthesized pyrazole compounds against GBM cells.

Methods: A series of pyrazole derivatives were synthesized and tested for their efficacy against GBM using MTT assays. Molecular docking studies were conducted to explore the binding interactions of these compounds with GBM receptors.

Results: Compounds 3 and 5 demonstrated significant anticancer activity, reducing cell viability more effectively than the control group. MTT assay results confirmed their potency. Molecular docking studies revealed strong binding interactions with GBM receptors, highlighting their potential as anticancer agents.

Conclusion: The study evaluated the anticancer activity of synthesized compounds on human GBM cells, with compounds 3 and 5 showing the most promising results. Pyrazole 3 significantly reduced cell viability at high concentrations, while both pyrazoles 3 and 5 required higher doses to achieve substantial effects, as indicated by their IC50 values. Molecular docking studies confirmed strong binding interactions with the GBM receptor, and the pharmacokinetic properties suggest their potential as anticancer agents. These results highlight compounds 3 and 5 as candidates for further investigation.

Background: We continue to struggle with the prevention and treatment of the influenza virus. The 2009 swine flu pandemic, caused by the H1N1 strain of influenza A, resulted in numerous fatalities. The threat of influenza remains a significant concern for global health, and the development of novel drugs targeting these viruses is highly desirable.

Objective: The objective of this study is to explore the inhibitory potential of terpenoid compounds against the Nucleoprotein (NP) of influenza A virus, which is a highly effective drug target due to its ability to facilitate the transcription and replication of viral RNA.

Method: In silico research was performed to identify potential inhibitors of NP. Molecular docking studies were conducted to assess the binding of terpenoid compounds to the active site residues of the target protein. The most promising hits were then subjected to molecular dynamics simulations to examine the stability of the protein-ligand complexes. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies and Lipinski's rule of five were employed to evaluate the drug safety and druglikeness of the compounds.

Result: Docking studies revealed that the terpenoid compounds bind strongly to the active site residues of the NP protein. Molecular dynamics simulations demonstrated the stability of the proteinligand complexes for the best-hit compounds. ADMET studies and Lipinski's filter indicated that the compounds exhibit desirable drug safety and drug-likeness profiles.

Conclusion: This work may contribute significantly to drug discovery and the development of therapeutic agents against the influenza A virus. The identification of terpenoid compounds that bind strongly to the NP protein and exhibit favorable drug-like properties through in silico studies provides a promising foundation for further research and the development of potential inhibitors targeting this critical viral protein.

Background: Oxidative stress is strongly linked to neurodegeneration through the activation of c-Abl kinase, which arrests α-synuclein proteolysis by interacting with parkin interacting substrate (PARIS) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). This activation, triggered by ataxia-telangiectasia mutated (ATM) kinase, leads to dopaminergic neuron loss and α-synuclein aggregation, a critical pathophysiological aspect of Parkinson's disease (PD). To halt PD progression, pharmacological inhibition of c-Abl kinase is essential. Despite three generations of tyrosine kinase inhibitors (TKIs) being explored for PD treatment, they present significant concerns including poor blood-brain barrier penetration, off-target effects, and severe side effects. Notably, there are currently no FDA-approved c-Abl kinase inhibitors in clinical usage for PD treatment, highlighting the urgent need for potent, safe, and cost-effective alternatives.

Objective: This study aims to identify potential c-Abl kinase inhibitors from plant-derived compounds with reported anti-Parkinson's potential and their derivatives using molecular docking, molecular dynamics simulations (MDS), and in silico pharmacokinetics and toxicity profiling.

Methods: Seventy-eight compounds sourced from literature were docked against c-Abl kinase using Maestro 12.5. The top three hit compounds, along with nilotinib (control drug), were subjected to drug-likeness, ADMET profiling using the AI Drug Lab server and 100 ns MDS using Desmond.

Results: Amburoside A, diarylheptanoid MS13, and dimethylaminomethyl-substituted-curcumin showed binding affinities close to nilotinib, with values of -12.615, -12.556, and -11.895 kcal/mol respectively, compared to nilotinib's -16.826 kcal/mol. The three plant-derived compounds exhibited excellent structural stability and favorable ADMET profiles, including optimal blood-brain barrier permeation Conclusion: The three hit compounds identified in this study show potential as c-Abl kinase inhibitors. Given the absence of FDA-approved c-Abl kinase inhibitors for PD, these findings are significant as they could contribute new therapeutic options for the treatment and management of PD. However, further in vitro and in vivo experiments are necessary to validate these findings.

Introduction: Epilepsy encompasses numerous syndromes characterized by spontaneous, intermittent, and abnormal electrical activity in the brain. Affecting about 1-2% of the population, it is estimated that approximately 30-40% of patients experience refractory epilepsy, which does not respond to traditional anticonvulsant drugs.

Aims: Therefore, developing novel, safe, and effective antiepileptic drugs remains a medical need. In this study, we synthesized a series of isoindoline-1,3-dione derivatives and evaluated their anticonvulsant effects.

Results: Compounds (2a-j) and (5) were obtained with yields ranging from 52-97%. These compounds were assessed for their protective effects on the following parameters: a) time to first seizure (seizure latency), b) seizure duration, and c) mortality rate post-seizure. The most active compound, (2a), increased seizure latency, reduced seizure duration, and lowered the mortality rate.

Conclusion: These findings indicate that compound (2a) is a promising new anticonvulsant prototype, offering an alternative to current anticonvulsant drugs.

Pyrazoline is a 5-membered ring that has two adjacent nitrogen. It has gained advanced attention from medical and organic chemists due to very low cytotoxic activities. It is applicable and more applied in research fields and has various pharmacological activities, including cardiovascular, anti-tumor, and anti-cancer properties. In this review, the main objective is to study the pharmacological aspects of pyrazoline and its derivative analogs. The present synthetic pyrazolines are better scaffolds, which show more biological and medicinal characteristics. These compounds exhibit diverse pharmacological activities, showcasing their potential as promising candidates for cancer therapy. Pyrazolines demonstrate remarkable anti-proliferative and apoptosis-inducing effects on cancer cells, attributed to their distinctive molecular structure. This review highlights the growing significance of pyrazolines in medicinal chemistry, emphasizing their role in designing novel anticancer agents. The multifaceted properties of pyrazolines offer a compelling foundation for further research, driving innovation in the quest for effective and targeted anticancer drugs.

The emergence of multidrug-resistant microbial strains poses a significant challenge to global public health. In response, researchers have been exploring innovative antimicrobial agents with enhanced efficacy and novel mechanisms of action. One promising approach involves the synthesis of hybrid molecules combining azetidinone and azole moieties, capitalizing on the respective antimicrobial properties of both structural elements. Natural and synthetic azetidinone derivatives hold a prominent position among medicinally significant compounds due to their varied and potent antibiotic activities. Interest persists in discovering new synthetic methods and refining existing ones, as well as applying these methods to create novel, biologically active azetidinone derivatives. Additionally, azoles are highly regarded in pharmaceuticals for their broad efficacy, tolerability, and oral availability. By merging these two pharmacophores, researchers aim to create compounds with synergistic or additive antimicrobial effects, potentially overcoming existing resistance mechanisms. Various synthetic strategies, including click chemistry and multicomponent reactions, have been employed to prepare these hybrid molecules efficiently. The antimicrobial potential of azetidinone-azole conjugates has been extensively evaluated against a spectrum of pathogens, including bacteria, fungi, and protozoa. These studies have demonstrated promising results, with several compounds exhibiting potent activity against both Gram-positive and Gramnegative bacteria, as well as clinically relevant fungal strains. Furthermore, SAR studies have provided valuable insights into the key structural features governing the antimicrobial properties of these conjugates, facilitating further optimization and rational design. In conclusion, the development of azetidinone-azole hybrids represents a promising avenue in the quest for novel antimicrobial agents. This study presents a comprehensive overview of recent advancements in synthesis and antimicrobial evaluation of azetidinone-azole conjugates.

Introduction: The marine habitat is a plentiful source of diverse, active compounds that are extensively utilised for their medicinal properties. Pharmaceutical trends have currently changed towards utilising a diverse range of goods derived from the marine environment.

Method: This study aimed to examine the inhibitory effects of bioactive chemicals derived from marine algae and bacteria. The identification of these compounds was carried out through the process of Gas Chromatography-Mass Spectrometry (GC-MS) profiling. Subsequently, these compounds were subjected to docking simulations against a specific set of target proteins that are known to be frequently overexpressed in three distinct types of cancer.

Result: From the docking results, the ligand 1,4:3,6:5,7-Tribenzal-beta-mannoheptitol was found to be effective against the proteins mTOR (PDB ID: 4JSV) and FGFR2 (PDB ID:6V6Q). The findings of this study highlight the significant benefits offered by the tool under investigation, which effectively enhances the efficiency of the docking procedures.

Conclusion: These compounds hold significant potential for further development and exploration in the field of cancer therapeutics.

Catechins, the main active components of tea polyphenols, boast remarkable antioxidant activities because of their unique structures. This translates to a range of potential health benefits, including fighting antibacterial, inflammation, and even cancers. However, extracting these beneficial compounds can be tricky as they're prone to degradation. Thankfully, recent advancements have yielded successful methods for isolating and purifying catechins, allowing us to obtain them in their purest form. The power of catechins isn't just theoretical. In vitro and in vivo studies have demonstrated promising results in treating various conditions like inflammation, cancer, neurodegenerative diseases, cardiovascular diseases, diabetes, and more. This review dives deep into the methods used to extract, isolate, and purify catechins. Additionally, it explores their potent antioxidant activities and exciting possibilities for future applications.