Medicinal Chemistry Research最新文献

This review presents an overview of the antitumor properties of various platinum(II) complexes of dithiocarbamates. It has been noticed that in several cases the activity is greater than cisplatin, while their toxicity level is low. The monofunctional platinum(II)-dithiocarbamate complexes comprising a labile chloride ligand possess the most effective cytotoxic behavior among the complexes discussed here. The bis(dithiocarbamato) complexes on the other hand show poor anti-proliferative potential. The complexes manifest their antitumor activity through DNA interaction that takes place via covalent bonding, intercalation or electrostatic interaction. The study of apoptotic activity in some cases suggests that these complexes trigger apoptosis, which causes the cell death. The induction of apoptosis is correlated with the generation of reactive oxygen species, the cell cycle arrest and the inhibition of NF-kB activity. The protective effects of dithiocarbamates against the platinum-induced toxicity have been explained. Dithiocarbamates were found to control the side effects of cisplatin and the anticancer activity of cisplatin was significantly improved in the presence of a dithiocarbamate. The study highlights that platinum(II) complexes of dithiocarbamates may be regarded as promising anticancer agents because of their effective cytotoxic properties and their potential to overcome cisplatin resistance.

Acetylcholinesterase (AChE) is indispensable for neurotransmission, while glutathione S-transferase (GST) plays a crucial role in cellular detoxification and protection. These enzymes are pivotal subjects in scientific investigations aimed at understanding neurological functions and maintaining cellular equilibrium. In pursuit of this objective, a set of disulfide–triazine hybrids (1, 2, and 3a–h) was effectively synthesized and methodically examined for their capacity to inhibit both AChE and GST (the Ki values for AChE range from 0.893 ± 0.117 μM to 7.961 ± 0.421 μM, while the IC₅₀ values fall within the range of 1.919–6.243 μM. For GST, the Ki values span from 2.093 ± 0.276 μM to 8.840 ± 1.934 μM, with IC₅₀ values ranging from 2.152 to 4.747 μM). After synthesizing the compounds and studying their biological effects, molecular docking analyses were conducted to understand how these compounds interact with target enzymes. This helped identify how the compounds bind and which amino acid residues are crucial for inhibition. The positive results highlight the potential of disulfide–triazine hybrids as strong inhibitors of AChE and GST, suggesting they could be further developed and optimized as therapeutic agents.

The classic cholinergic hypothesis was considered as the successful hypothesis due to the marketed drugs (donepezil, rivastigmine, and galantamine). The development of selective AChE inhibitor still was a promising strategy for the treatment of Alzheimer’s disease (AD). Herein, 29 novel rivastigmine derivatives was rationally developed as selective AChE inhibitors for treating AD. The target compounds were designed and evaluated through AChE/BuChE inhibition, reversibility study, and neuroprotective effect. The results in vitro showed that compound 9a showed the best eeAChE inhibitory potency (IC₅₀ = 1.78 μM) and weak BuChE inhibitory potency, suggesting that compound 9a was a selective AChE inhibitor. The molecular docking offered possible mechanism for its high AChE inhibitory potency. The further study indicated that compound 9a was a pseudo-irreversible eeAChE inhibitor. Furthermore, 9a demonstrated significant neuroprotective effect on L-Glu-induced HT22 cells injury. Further, 9a presented favorable predicted drug-like property. Therefore, 9a was a promising selective AChE inhibitor for treating AD.

Indole scaffolds are well-documented for their biological accessibility and broader therapeutic applications. The cellular interaction of the indole moiety and its intrinsic effects on cell transduction and proliferation mechanisms in cancer biology have been widely acknowledged. Despite available reports on anticancer indoles, the structural insights of indole compounds in targeting drug-resistant breast cancer have yet to be elaborated upon. Breast cancer is emerging as the most common cancer in women worldwide, affecting more than two million women annually. Considering the optimistic evidence found in recent studies on the druggability of indole derivatives for breast cancer, this review presents indole compounds of interest with anti-breast cancer activity, along with their structural insights and mechanisms. This review updates several interesting facts related to the indole interacting pathway suitable for drug-resistant breast cancer. Furthermore, the clinical pharmacokinetic and toxicity reports of these compounds are very impressive. This integrative view of indole compounds will undoubtedly pave the way for further exploratory research in the discovery of newer indole-based chemotherapeutics as efficacious leads for breast cancer.

Dipeptidyl peptidase 4 (DPP-4), well known as the T-cell antigen CD26 enzyme which, was discovered in the year of 1966 by Hopsu-Havu and Glenner. The enzyme gained considerable attention due to its vital functions, such as (1) deactivation of the incretin hormone, which is responsible for insulin catabolism, (2) hydrolyzes of opioid peptides engaged in pain modulation, etc. Moreover, DPP-4 also acts as a carrier protein and ligand for a variety of extracellular and intracellular substrates. The Finding of DPP-4 inhibitors is the newer approach to treating numerous disorders/ diseases, for example, coronary heart disease, heart failure, stroke, and Diabetes mellitus (DM). The outcomes of studies carried out in the past few decades revealed that Gliptins (DPP-4 inhibitors) is a more promising candidate than conventional hypoglycaemic agents, as the former can be taken in monotherapy once a week or conjointly with another hypoglycaemic agent. By considering all favorable properties of DPP-4 inhibitors, this excerpt was written with the primary focused on the clinically approved, orally acting Gliptin class of drugs, with an emphasizing on their conventional, modern as well as patented methods of intermediates and final product development.

The discovery of novel antibacterial agents holds promise in mitigating the escalating threat of antimicrobial resistance (AMR). Guided by the structure-activity relationships (SAR) of our lead compound 1 against MRSA, we developed novel anti-MRSA compounds with a repositioned lipophilic tail from para to meta position. This strategic modification resulted in compounds 10e and 10l exhibiting equivalent activity to lead compound 1 (MIC = 4 µg/ml) against the highly clinically important strain MRSA USA300. Additionally, both compounds demonstrated a low propensity for resistance development and an acceptable cytotoxicity profile. However, their systemic administration was poorly tolerated. The in vivo study in a murine model revealed modest activity in the skin model but an acceptable effect in controlling systemic dissemination.

Traditional Chinese medicine (TCM) holds distinctive advantages in the management of Alzheimer’s disease. Nonetheless, a considerable gap remains in our understanding of its pharmacologically active constituents. In this study, we harnessed the potential of deep learning models to swiftly and precisely predict drug-target interactions. We conducted a systematic screening of cholinesterase (ChE) inhibitors from an extensive array of TCM ingredients, followed by rigorous validation through in vitro experiments. We constructed both a drug-target interactions (DTI) model and a blood-brain barrier permeability (BBBP) model, with both models achieving an AUPRC score exceeding 0.9. Subsequently, we conducted a screening process that identified six compounds for in vitro ChE inhibitory assay. Notably, all six compounds exhibited a robust inhibitory effect on acetylcholinesterase (AChE), while four of the six compounds demonstrated potent inhibitory activity against butyrylcholinesterase (BChE). Our findings underscore the promise of leveraging deep learning to discover inhibitors from TCM.

Sirtuins are a group of enzymes known as class III histone deacetylases that catalyze the deacetylation reaction and are presented across various species. In humans, they exhibit seven isoforms known as SIRT1–7, localize in distinctive cellular compartments, the nucleus (SIRT1, 6, 7), cytoplasm (SIRT2), and mitochondria (SIRT3, 4, 5). They play crucial roles in metabolism, DNA repair, and rRNA transcription. As research on sirtuins has expanded, there has been increased interest in identifying sirtuin modulators that may hold therapeutic implications in various diseases. Despite the identification of numerous sirtuin modulators, only few have entered clinical trials due to selectivity and safety concerns. Hence, subsequent research is needed to understand their mechanisms and ensure their safety profiles. This review summarizes experimental data and the status of sirtuin modulators reported from 2013 to current, aiming to contribute to the advancement of sirtuin modulation research and the identification of promising candidates for future development.