European Journal of Medicinal Chemistry Reports最新文献

This review explores the non-random distribution of chemical novelty among marine invertebrate phyla, with a particular focus on Porifera (sponges), which have exhibited the highest average count of novel natural products per species since 1990. Sponges, considered the oldest multicellular animals, boast approximately 15,000 species, with 8553 officially recognized. They are integral to marine ecosystems and have ecological, economic, and biopharmaceutical significance. The review outlines the structure and habits of sponges, their historical use, and their prevalence in various marine and freshwater habitats. Notably, sponges are recognized as key sources of marine natural products, with their potential medicinal applications extensively studied. Lead compounds derived from sponges have yielded marine pharmaceuticals, including cytarabine, vidarabine, and eribulin mesylate, approved for anticancer and antiviral purposes. Ongoing clinical studies involve novel sponge derivatives such as gemcitabine, hemiasterlin, discodermolide, and PM060184. The review underscores the global interest among researchers in natural product chemistry and pharmaceutical sciences in investigating marine sponges for medication development. The authors conducted a comprehensive literature review from 2000 to 2023, summarizing the chemistry and pharmacological activities of porifera-derived alkaloids based on 212 research papers. The chemical distribution section emphasizes the oceans as a vast repository of unexplored chemical diversity, with sponges yielding approximately 413 alkaloids from 2000 to 2023. Overall, the review provides a comprehensive overview of the chemical and pharmacological diversity of porifera-derived alkaloids, highlighting the importance of sponges as valuable subjects for chemical investigations with potential implications for medication development.

During recent times, the delivery of the medications to the colon has seen more interest by the researchers, as it proved to be providing both options for treating local colon-related conditions and a route for systemic delivery of the various other types of medications. For these to happen, the medication has to provide protection from severe conditions in the stomach and small bowel, which either degrade the medication or may cause its premature release and uptake in the upper part of the digestive track. This review describes the various roles of microspheres as a colon-targeted drug delivery device (CTDDD). Through these review, we try to provide thorough information about the effects of the physiology of the colon. Also, we made an effort to highlight different mechanisms of colon targeting. Along with these, we have pointed out some of the important evaluation factors for carrying out a thorough investigation about the physicochemical and pharmaceutical properties of microspheres for targeting the colon. Also, we exchange views about the applications of microspheres as CTDDD in different diseases and disorders of the colon. Plus, we discuss the different challenges that occur during the formulation and targeting of these microspheres. At last, we share our thoughts on the possibilities in the near future in these domains, which will help in changing the scenario of how we can treat colon-related problems.

The antiapoptotic protein BCL2 is overexpressed in several cancers. It contributes to prolonged cell survival and chemoresistance, making it an excellent target for targeted cancer therapy. Over the years, several BCL2 inhibitors have been investigated extensively for their anticancer potential; however, most of them were abolished before clinical use due to their pan activity. There is only one FDA-approved BCL2-specific inhibitor, Venetoclax, currently used in clinics. Previously, we reported the characterization and development of a novel BCL2 inhibitor, Disarib, which is selective against BCL2 and predominantly binds to the BH1 domain of BCL2. Importantly, the efficacy of Disarib was equally good or better than Venetoclax in various in vitro and in vivo assays. In the present study, we report the development of a scalable and practical method for the large-scale synthesis of Disarib to support the ongoing pre-clinical studies. The parameters of each step were optimized through prior knowledge, helping in improving the yield and purity to 98.8 %. Further, we compared the efficiency of a large-scale synthesized Disarib in a GLP-certified laboratory with that of an in-house synthesized Disarib. The results showed that the biological activity, including Disarib-induced cytotoxicity and cell cycle progression, were comparable. Besides, the tumor regression efficacy and pharmacokinetics analysis of Disarib have shown comparable results when Disarib synthesized in both routes were tested. Thus, a robust and scalable synthetic pathway of Disarib has developed to address small-scale synthesis's limitations in supporting their expanded applications and use.

1,3,4-Oxadiazine is a six-membered heterocyclic ring containing two nitrogen atoms and one oxygen atom. It is an important structural motif that has gained significant interest in the fields of pharmaceuticals, agrochemicals, and materials science due to its unique properties and versatile applications. The synthesis of 1,3,4-oxadiazine derivatives can be achieved through various methods such as cyclization of α,β-unsaturated nitriles, the reaction of hydrazides with carbonyl compounds, and condensation of nitriles with amidoximes. These synthetic routes offer a wide range of structural diversity and functionalization, making 1,3,4-oxadiazine derivatives attractive candidates for drug discovery and development. 1,3,4-Oxadiazine derivatives have been shown to possess a broad range of biological activities, including antitumor, antimicrobial, antiviral, and anti-inflammatory properties. During the literature search, it was observed that no review focuses on the SAR-based discussion of 1,3,4-oxadiazine ring-containing molecules used to treat various diseases. In order to address this issue in this review, we have discussed the synthetic route, US-granted patents, and structure-activity relationship (SAR) of the biologically active compound containing a 1,3,4-oxadiazine ring, as well as their current limitations and future prospects.

Alzheimer's disease (AD), the main dementia type accounting for over 70 % of the entire dementia population and exhibits progressive decline in memory and executive function. AD pathology is characterized by amyloid fibrils and neurofibrillary tangles. Acetylcholinesterase (AChE), an enzyme involved in the hydrolysis of the neurotransmitter acetylcholine, consistently colocalizes with the amyloid deposits is characteristic of Alzheimer's disease and may contribute to the generation of amyloid proteins. AChE is a potent amyloid-promoting factor as compared with other associated proteins. AChE inhibitors play a vital role to prevent the formation of toxic oligomeric form of amyloid peptide. Recent studies have reported that acetylcholinesterase inhibitors (ChE-Is) are present in plants, fungi, and marine products. Some cholinesterase inhibitors, obtained from plant source such as rivastigmine, donepezil, and galantamine, used in the treatment of AD, offer an alternative approach to alleviate its symptoms by reducing Aβ.

Due to limited efficacy of currently available drugs for AD, there is huge potential of phytomedicines for the treatment of AD. Medicinal herbs and herbal drug preparations have traditionally been used to treat neurological disorders such as AD by exhibiting its anti-inflammatory and neuroprotective properties. Phytomedicines containing flavonoids, polyphenols, and other naturally occurring antioxidants crosses the blood-brain barrier and protect neurons from oxidative stress. As compared to synthetic drugs, phytomedicines have fewer side effects. Therefore, recent research is focused to explore the potential of phytomedicines and develop it as effective treatment for AD. In our review, we summarized the pathology of AD, amyloid-deposition, role of Acetylcholinesterase, potential of phytoconstituents with acetylcholinesterase inhibitory activity for AD treatment.

In recent years, the emergence of d-ribose l-cysteine (DLRC) as a potential treatment regimen for neuro-endocrinopathy, reproductive dysfunction and cardio-metabolic syndrome has been gaining attention among medical professionals. This review discusses the safety issues associated with d-ribose l-cysteine and its potential in treating neurological damage, reproductive dysfunction, endocrine diseases, Chondrocyte degeneration, and cardio-metabolic syndrome. Electronic databases were searched for information on d-ribose-l-cysteine and its potential effects on neuroendocrine disorders, using various search terms. In vitro and in vivo studies were examined for any links between d-ribose-l-cysteine and neuroendocrine protection. This review seeks to analyze the available evidence for such a treatment regimen, with particular emphasis on its efficacy, safety profile, and limitations. A review of preclinical studies related to d-ribose l-cysteine and the aforementioned conditions was conducted. The studies demonstrate that the treatment is safe as well as demonstrates promising results in terms of efficacy. This review provides an overview of available evidence for the use of d-ribose l-cysteine as a potential treatment option for neurological damage, reproductive dysfunction, endocrine diseases, Chondrocyte degeneration, and cardio-metabolic syndrome, providing a rationale for further investigation into this therapy. DRLC plays an important role in neuroendocrine and reproductive functions as well as cardiometabolic functions in animal model. Its assessment provides essential information that could guide treatment strategies aimed at improving male reproductive potential. Taken together, these recent advances highlight a future therapeutic intervention in assessing male physiological functions.

Human immunodeficiency virus, a retrovirus, causes AIDS, a chronic immune system disease. HIV interferes with the ability of our body to combat disease and infection by weakening our immune system. An essential enzyme necessary for HIV replication is reverse transcriptase (RT). RT inhibitors (RTIs) are a class of antiretroviral drugs that target HIV's RT enzyme, blocking its ability to convert viral RNA into DNA. The RT-1 enzyme has been found to be inhibited by imidazole. It attaches to the RT-1 enzyme's active site and prevents it from performing its usual activity. As a result, viral replication is inhibited, which can eventually aid in slowing the course of HIV and other retroviral diseases. A computational tool allows researchers to simulate and analyze the drug's behaviour in a virtual environment, providing valuable insights into its pharmacological properties, efficacy, and safety. QSAR modelling uses machine learning methods to create predictive models from datasets of chemical substances and the accompanying biological activity. Here, a comparative analysis of the model performances by four different algorithms for the Imidazole scaffold are reported. The algorithms of Support Vector Regression (SVR), Random Forest Regression (RFR), Decision Tree Regression (DTR) and Hist Gradient Boosting Regression (HGBR) have given promising results with the R² value of 0.905, 0.993, 0.688 and 0.921 respectively for the train sets and for the test set 0.843, 0.977, 0.567 and 0.880. The best performed RFR model have been validated using developed RFR codes for randomly selected compounds and it shows the error percentage of about 0.151% only. From the R² values, it is observed that the RFR and HGBR models show a better fit with the variables compared to the other models thereby making them the potential models for predicting the activity of novel anti-viral compounds.

Given the growth in drug-resistant and inactive cases of tuberculosis, it is imperative to develop novel, potent chemicals to treat this deadly illness. Compounds containing oxadiazole are one such class of chemicals that could be taken into consideration to meet this requirement. The biological action of compounds with a 1,3,4-oxadiazole ring in their structure is diverse. The numerous functions of a five-member heterocyclic ring have sparked interest of medicinal and synthetic organic chemists involved in the design of novel molecules. The development of the small and straightforward 1,3,4-oxadiazole nucleus, which is found in a variety of compounds with significant pharmacological capabilities like antitubercular and is intended to assess novel goods, has a lot of potential. This review article highlights the various approaches used to generate the 1,3,4-oxadiazole nucleus, the targeted activity of 1,3,4-oxadiazole derivatives and their structure activity relationship to produce potential antitubercular drugs.

In this study, a series of nine novel heterocyclic compounds were synthesized through a concise three-step reaction process. The synthesis involved Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione or rhodanine ring-system. Comprehensive physicochemical and spectral analyses, including FTIR, Mass, ¹H NMR and ¹³C NMR, were performed to characterize the synthesized compounds. The synthesized derivatives were subjected to evaluation for their potential in various therapeutic domains. In-vivo anti-diabetic activity was assessed diabetes induced wistar rats, anti-inflammatory effects were gauged using the carrageenan and formalin induced rat paw edema model. Additionally, the in-vitro PPAR-γ modulatory activity, glucose uptake by using Saccharomyces cerevisiae and rat hemidiaphragm and cyclooxygenase inhibitory activity along with scavenge free radicals was tested by FRAP and DPPH method. According to the potential binding patterns of the most potent anti-diabetic compounds, namely 7a and 13a with the active sites of target PPAR-γ (PDB ID: 5U5L), was obtained through molecular docking using Schrodinger’s Glide model. Among the tested compounds, the compound 13a demonstrated significant antidiabetic activity with reduction in blood glucose levels (108.5 ± 2.171 mg/dL), comparable to the effect of pioglitazone (101.66 ± 0.95 mg/dL), similarly anti-inflammatory activity at fourth hour paw volume 93.6% and thickness at 3.99 ± 0.076 mm, respectively closer to that of standard drug diclofenac sodium (91.2% and 4.7 ± 0.057 mm) in carrageenan-induced paw edema in rat. The compound 13a displayed promising COX-2 inhibitory activity (IC₅₀ = 7.82 μM) and DPPH antioxidant activity showcasing its multifaceted therapeutic potential. This study not only presents multi-targeting approach and highlights the significant potential compounds as a lead molecule for further therapeutic development.

Globally, millions of infections that are resistant to antimicrobial agents are reported annually, leading to more than 700,000 fatalities. Among all, challenges arise particularly from nontuberculosis mycobacterial (NTM) and Gram-negative bacteria, as they exhibit limited treatment options in light of increasing reports of multi-drug resistant strains.

Clofazimine (CFZ) is an antimycobacterial medication used to treat leprosy, and it is also known for its side effect of inducing skin pigmentation. The use of CFZ and its analogues against a broad range of Gram-negative bacteria has not been extensively investigated. In this study, we designed, synthesized and studied 11 CFZ analogues and identified examples with comparable or improved in vitro anti-bacterial activity relative to that of CFZ itself. This is the first report demonstrating in vitro activity of CFZ and its analogues against Neisseria species. The results of these studies may facilitate the development of CFZ analogues with limited side effects in humans.