Medicinal Chemistry Research最新文献

The advent of nanosensing technologies marks a significant advancement in medicinal chemistry, particularly in the detection and monitoring of therapeutic agents such as doxorubicin. This review aims to elucidate the development of cutting-edge biosensor technologies specifically tailored for the sensitive and selective detection of doxorubicin, a cornerstone chemotherapeutic agent. We critically analyze various recently developed nanosensors, including electrochemical sensors and optical sensors, highlighting their distinct mechanisms, advantages, and limitations. Unlike previous literature, this review synthesizes current research findings to provide a comprehensive overview of how these innovative nanosensing platforms can enhance drug monitoring, improve therapeutic outcomes, and support personalized medicine approaches. By addressing the existing challenges in doxorubicin detection, our findings underscore the transformative potential of integrating nanotechnology with biosensing applications, ultimately contributing to more effective cancer treatment strategies.

DNA polymerase theta (Polθ or POLQ) is an attractive target for treating BRCA-deficient cancers. In the present work, several computational approaches were employed for the design and discovery of novel POLQ helicase domain inhibitors. A dataset was constructed by curating a total of 781 known inhibitors, which were used to develop binary classification models using random forests to distinguish between highly and weakly active inhibitors. The Matthews correlation coefficient of the consensus model reached 0.771 for the test set. A virtual screening procedure of 3.4 million molecules was conducted based on shape similarity and predictions from the consensus model to identify four hits and a favorable benzothiazole moiety. A molecular generation model was trained using molecules from both the curated dataset and the identified hits to generate potential inhibitors, which were subsequently predicted by the consensus model. Finally, eight compounds were selected and synthesized for biochemical testing, leading to the identification of compound 19, which had a novel scaffold and acceptable potency: inhibition rates of 80.7% at a concentration of 100 nM and 39.5% at a concentration of 10 nM. Compound 19 could serve as a suitable starting point for further optimization efforts in medicinal chemistry.

Machine Learning, Virtual Screening, Molecular Generation, Compound Synthesis, and Biochemical Testing in the Discovery of POLQ Helicase Domain Inhibitors.

Fatigue is a widespread issue that affects both mental and physical performance, yet effective treatments remain limited. This study focused on developing and evaluating new synthetic adaptogens—compounds designed to enhance endurance and reduce fatigue. We synthesized and tested derivatives of 3,7-diazabicyclo[3.3.1]nonanes (bispidine) and 1,3-diazaadamantanes, incorporating monoterpenoid fragments to improve their pharmacological properties. Using SwissADME and PreADMET tools, we predicted that most of these compounds would be well-absorbed in the gastrointestinal tract and capable of crossing the blood-brain barrier. Among them, compound 2, a 1,3-diazaadamantane derivative, stood out for its strong antifatigue effects at 10 mg/kg in swimming and running endurance tests in in vivo experiments with mice, even outperforming the reference drug bromantane. Acute toxicity tests showed that this compound has a high safety margin, with an LD₅₀ value 237.5 times greater than its effective dose. Further analysis of structure-activity relationships revealed that monosubstituted 1,3-diazaadamantane derivatives had the most promising effects, suggesting that specific chemical modifications can enhance performance. These findings indicate that this new class of synthetic adaptogens could offer a safe and effective way to combat fatigue, making them strong candidates for further pharmacological research and potential therapeutic use.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which the multi-target-directed ligand (MTDL) strategy offers a promising therapeutic approach. In this study, a caffeic acid-dopamine hybrid was designed and evaluated for its multifunctional activities. Subsequently, two derivatives incorporating a carbamate fragment were synthesized. Among these, compound 3 demonstrated excellent antioxidant activity, significant inhibition of self-induced Aβ_1–42 aggregation, anti-inflammatory properties, and neuroprotective effects, though it exhibited weak cholinesterase inhibition and limited blood-brain barrier (BBB) permeability. In contrast, the derivative TM-2 showed potent butyrylcholinesterase inhibition (IC₅₀ = 0.36 μM), potential antioxidant activity, and significant inhibition of self-induced Aβ_1–42 aggregation (48.9%). TM-2 also reduced NO and IL-6 levels, provided significant anti-inflammatory effects, and exhibited neuroprotective effects against Glu-/Aβ_25–35-induced injury in PC12 cells. Importantly, TM-2 demonstrated BBB permeability in vitro and significantly improved memory impairment in a scopolamine-induced mouse model. These findings suggest that TM-2 is a promising multifunctional agent for the treatment of AD.

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, plays a pivotal role in the metabolism of endogenous reactive aldehydes and functions as a crucial defense mechanism against oxidative stress. The inactive ALDH2 rs671 polymorphism has been implicated in an elevated risk of various cardiovascular diseases, such as myocardial infarction, cardiac arrhythmia, coronary heart disease, and heart failure. Alda-1 is currently the most widely recognized ALDH2 activator and its anti-heart failure properties have been extensively reported. However, Alda-1 possesses limitations in terms of pharmacokinetic properties, safety, and bioavailability, which hinder its broad clinical application. Therefore, the development of novel ALDH2 activators represents a promising novel therapeutic approach. In this study, we employed a bioisosteric substitution strategy to modify the amide bond of Alda-1. Consequently, a selenamide derivative A8 was discovered to exhibit potent ALDH2 activation activity at the submicromolar level (ALDH2*1: EC₅₀ = 0.21 ± 0.03 μM; ALDH2*2: EC₅₀ = 0.31 ± 0.03 μM) and showed reduced cytotoxicity compared to Alda-1 in H9c2 and HepG2 cell lines. Furthermore, A8 provided potent protection of cardiomyocytes and showed enhanced efficiency in metabolizing endogenous reactive aldehydes. Our findings present A8 as a valuable lead compound for advancing the development of ALDH2 activators, thereby offering new avenues for cardioprotective therapies.

The global burden of tuberculosis is on the rise and continues to be alarmingly high, with a notable prevalence of multidrug-resistant disease. Despite a promising drug development pipeline, the levels of resistance to these therapeutics remain significant, underscoring the need for new, innovative drugs to tackle this clinical issue. Benzoxadiazoles and their derivatives have become a valuable foundation for the development of next-generation antibacterial, antifungal, and anticancer agents. Herein, we explore the benzoxa-[2,1,3]-diazole scaffold as a promising framework for antimycobacterial development. Building on prior work, thirty-two amino acid hydrazide derivatives were synthesised using a modular approach, allowing variation of both the aryl hydrazine and amino acid moieties. These analogues were evaluated for activity against wild-type, isoniazid-resistant, and multidrug-resistant mycobacterial strains using the REMA assay, with several analogues demonstrating notable inhibitory activity. Overall, the series of novel benzoxa-[2,1,3]-diazole amino acid hydrazides demonstrates that through manipulation and optimisation of the amino acid hydrazide moieties, it is feasible to engineer potent compounds with improved antimycobacterial activity against both wild-type bacteria and, crucially, drug-resistant strains of the disease.

The synthesis of (1H-1,2,3-triazol-4-yl)-1,2,4-triazolazine derivatives was achieved via a multi-step synthesis starting from 1H-1,2,3-triazole-4-carboxylic acids, followed by acylation and ring closure under the influence of POCl₃. The title compounds were tested for cytotoxicity against a range of cancer cell lines, including A549 human lung carcinoma, HCT116 colon carcinoma, Jurkat T-leukemia, and KB3-1 human cervical carcinoma. The compounds demonstrated varying degrees of activity, with several showing potent cytotoxic effects, particularly against human lung carcinoma A549 and human leukemia Jurkat T-cells. The results suggest that ring closure significantly influences the bioactivity of the compounds, enhancing their cytotoxic properties. The study indicates the potential of (1H-1,2,3-triazol-4-yl)-1,2,4-triazolazine derivatives as promising candidates for cancer therapy, especially those with specific substituent patterns that enhance their antiproliferative effects.

Thirty-three derivatives of chrysin were designed and synthesized to evaluate biological activities. All compounds were characterized using spectroscopy techniques (IR, ¹H NMR and ¹³C NMR). Moreover, twelve new derivatives were fully characterized via the HRMS technique. The derivatives and the lead compound, chrysin (1) were screened against HDAC inhibition at 100 µM. Three derivatives (C22, C23 and C24) demonstrated the most effective inhibition against HDACs with the IC₅₀ values as 27.13 ± 2.74 µM to 47.47 ± 1.13 µM. Furthermore, the HDAC8 inhibitory activity of compounds C22 and C23 (IC₅₀ = 75.37 ± 3.42 µM and 79.74 ± 0.41 µM, respectively) were more potent than that of chrysin (1) (IC₅₀ > 100 µM). A molecular docking study found that the most active compound C22 was more selective with HDAC8 (ΔG = −8.54 kcal/mol) than other isoforms (HDAC1, 2 and 3). The carboxyl moiety of the strongest derivatives plays an essential role in chelation with the Zn²⁺ cofactor based on metal chelation assay. The Western blot assay confirmed that compounds C23 and C24 were the best HDACis. The most selective HDAC8 inhibitor, compound C22, showed the IC₅₀ value as 13.04 ± 1.08 µM against colon cancer cell lines (HCT-116), whereas compound C24 exhibited the lowest IC₅₀ value as 11.96 ± 0.18 µM against the same cancer cell lines. The ClogP values of all derivatives were acceptable for oral administration (ClogP = 3.57 to 4.26). Therefore, the chrysin derivatives C22, C23 and C24 showed potential for further development as anti-cancer candidates.

Palbociclib is a selective cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor that emerged as a significant therapeutic agent in the treatment of hormone receptor-positive, HER2-negative breast cancer. This review comprehensively highlights the pharmacological significance of palbociclib and its recently developed derivatives, focusing on mechanisms of action, chemical synthesis strategies, pharmacological profile and potential benefits in cancer treatment. We explored the rationale behind structural modifications and chemical derivatization of palbociclib that have been developed to enhance its therapeutic efficacy and mitigate side effects. This review offers an update on the latest advancement in palbociclib derivatives and explores their potential to improve therapeutic efficacy with minimal side effects. The detailed analysis of recent developments and ongoing research will support the designing of more efficient CDK4/6 inhibitors and provide direction in development of future cancer treatment. We anticipate that the information provided in this review will be beneficial to readers and scientist working towards development of effective cancer treatment specifically towards next-generation CDK4/6 inhibitors with improved therapeutic and safety profiles.

Cancer combination therapy is a novel strategy to circumvent drug resistance in highly metastatic and advanced malignancies. To this end, we designed and synthesized a series of dual-targeting compounds that target tubulin and HDAC6 simultaneously. Out of them, compound named as 6-4 possessed potent inhibitory activity against tubulin polymerization and strong antiproliferative activity to the cancer cell lines tested. 6-4 was able to inhibit tubulin polymerization and disrupt the microtubule network of tumor cells. Significant downregulation of tubulin deacetylation was also observed after the treatment of 6-4 which indicated its inhibition toward HDAC6. Mechanism studies demonstrated that 6-4 could arrest cell cycle in G2/M phase and induce apoptosis in a dose-dependent manner. In addition, 6-4 can suppress metastasis of Hela cells, and significantly inhibit the formation of HUVEC tubes. All these results suggest that 6-4 should be a promising candidate for the treatment of cancer.