Future medicinal chemistry最新文献

Chemotherapeutics play a pivotal role in cancer therapy, but the limitations, such as multidrug resistance, poor selectivity, and severe systemic toxicity, urgently drive the development of novel anticancer agents. Indole derivatives, as privileged pharmacophores in oncology, exhibit inherent anticancer activity by targeting key signaling pathways. The thiazole moiety is widely integrated into anticancer drug design due to its ability to enhance binding affinity to biomolecular targets and improve pharmacokinetic properties. The hybridization of indole with the thiazole scaffold has emerged as a promising strategy to synergize the biological activities of individual pharmacophores, yielding indole-thiazole hybrids with enhanced antiproliferative efficacy, improved target selectivity, and reduced cytotoxicity toward normal cells. This review systematically summarizes the latest advances in the anticancer potential of indole-thiazole hybrids developed since 2021. To delineate the key molecular features that govern the anticancer potency of indole-thiazole hybrids, this review further presents a detailed structure-activity relationship (SARs) analysis; complementing these SARs insights, the review also conducts an in-depth exploration of the mechanisms of action, including their interactions with key biomolecular targets and modulation of oncogenic signaling pathways, to elucidate the molecular basis for their enhanced anticancer efficacy and lay a foundation for rational drug design of next-generation candidates.

Ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial regulator of the DNA damage response, supporting replication fork stability, enforcing cell-cycle checkpoints, and coordinating repair mechanisms. Tumor cells, which often experience oncogene-induced replication stress, rely more heavily on ATR signaling, presenting a potential therapeutic target for anticancer drug discovery and development. Over the last decade, intensive medicinal chemistry efforts have generated a broad pipeline of ATR inhibitors, including ceralasertib, elimusertib, camonsertib, berzosertib, ART0380, and gartisertib, many of which are in Phase I/II clinical trials. These compounds effectively disrupt checkpoints, induce replication catastrophe, and work synergistically with PARP inhibitors, topoisomerase poisons, platinum-based chemotherapies, radiotherapy, and immunotherapy. Although promising, challenges such as hematologic toxicities and resistance mechanisms persist. Future research aims to improve patient selection through biomarkers like replication-stress signatures, RAD51 foci tests, and liquid biopsy DNA damage markers; develop advanced modalities including brain-penetrant scaffolds, PROTAC degraders, and dual ATR/PARP or ATR/HDAC inhibitors; and optimize intermittent dosing to expand therapeutic windows. Incorporating these strategies into adaptive platform trials with pharmacodynamic markers and patient-centered outcomes will speed up translation. Overall, ATR inhibitors highlight progress in DNA damage response therapies, from understanding mechanisms to biomarker-driven clinical use, with the potential to revolutionize treatment across various cancers.

Metal-metal interactions play a crucial role in determining the molecular geometry, stability, and biological activity of many compounds. In recent years, organometallic compounds have gained significant importance in medicinal chemistry due to their structural and functional properties in treating various ailments. A virtually limitless number of structures and conformations can result from the enormous range of oxidation states, coordination numbers, and geometries that metal ion coordination complexes and organometallic compounds can adopt, depending on their nature. Understanding the types of metal-metal bonds formed by various elements across the periodic table, their thermodynamic and electronic properties, and their influence on physicochemical properties such as lipophilicity, solubility, and bioavailability becomes essential. Various drug design strategies employ approaches that involve metal-metal bonding, supported by ligand engineering, bridging ligands, and supramolecular or bimetallic complexes. However, off-target effects, toxicity, complexity, stability issues and regulatory considerations pose as key challenges in this task. Future directions focus on emerging applications of metallopharmaceuticals in cancer, antibacterial therapies, as well as their integration with nanotechnology and advanced drug delivery. This review highlights the insights into the concepts of metal-metal interactions, which are crucial for expanding the scope and applications of medicinal chemistry.

Aims: This study aimed to develop a robust machine learning (ML)-based quantitative structure-activity relationship (QSAR) model to identify potential drug candidates active against multidrug-resistant Salmonella typhi.

Materials & methods: A curated ChEMBL-derived dataset was assessed for modelability, yielding a high MODI value of 0.89. A hybrid feature selection workflow was applied to retain 20 chemically interpretable molecular descriptors, and eight diverse ML classifiers were systematically trained and benchmarked.

Results: The Support Vector Machine (SVM) model achieved the highest performance (MCC = 0.61, ROC-AUC = 0.90) on the hold-out test set.

Conclusions: Overall, rigorous ML-QSAR modeling offers a reliable and efficient framework for virtual screening and prioritization of novel anti-S. typhi agents discovery.

Aims: Antiplatelet drugs are commonly used to prevent cardiovascular diseases (CVD). However, they are associated with side effects, highlighting the need for safer and more effective alternatives. The purpose of the present work was to evaluate the antiplatelet potential of a series of Morita-Baylis-Hillman (MBH) adducts and to test their safety.

Materials & methods: The antiplatelet activity was assessed using microplate aggregometry and confirmed by the turbidimetric method, utilizing platelet-rich plasma (PRP) from healthy volunteers. Next, we examined the effect of the selected compounds on platelet secretion, GPIIb/IIIa complex activation, and blood coagulation. The safety of the antiplatelet agents was evaluated by testing their cytotoxicity on platelets and erythrocytes.

Results: Among the tested compounds, Al4, OAc1, OAc2, OAc3, R12, R22, R32, and R52 demonstrated potent inhibition of Adenosine 5'-diphosphate (ADP)-induced platelet aggregation, with IC₅₀ values ranging from 0.042 to 0.4 mM. The selected compounds also inhibited platelet aggregation induced by arachidonic acid (AA) and collagen. Notably, they significantly inhibited P-selectin expression and GPIIb/IIIa activation, without affecting coagulation parameters. Toxicological evaluation showed that these compounds did not induce hemolytic or cytotoxic effects on human erythrocytes or platelets.

Conclusion: Collectively, these results identify MBH adducts as promising scaffolds for the development of novel selective antiplatelet agents.

Many polycyclic compounds have been reported to possess a significant pharmacological activity, among them spirocyclic derivatives. Natural alkaloids containing spiro-carbons are widely distributed in nature and exhibit diverse pharmacological properties, such as antitumor, antimycobacterial, antitubercular, antimalarial, and antimicrobial activities, and others demonstrated by theoretical studies, such as molecular docking. In addition to their medical uses, some spirocompounds find applications in agriculture and industry practices. This review is an endeavor to highlight the current methods to synthesize spirocyclic compounds and their pharmacological interests reported since the end of the twentieth century.

This collection of studies summarizes findings from various investigations into pyridine nuclei and their potential as anticancer agents. Understanding the role of pyridine-containing compounds in the development of effective anticancer drugs requires a thorough examination of their Structure-Activity Relationship (SAR). The structural diversity and key biological targets of pyridine derivatives have generated considerable interest. By presenting significant discoveries from multiple studies, this compilation aims to provide a comprehensive overview of the SAR principles that influence the anticancer activity of pyridine-based compounds. Through a detailed analysis of the SAR, we highlight the essential structural features that affect the anticancer efficacy of these derivatives. A key focus of this paper is the development of quantitative SAR models to predict the anticancer activity of novel pyridine analogues. Additionally, it includes the most recent data on the most active and potent derivatives, as well as the targeted cell lines.

Poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in DNA damage repair and preservation of genomic integrity, making it promising target in oncology. PARP-1 inhibitors (PARP-1i) employ synthetic lethality to specifically target cells with deficiency in homologous recombination repair, such as those with BRCA1/2 mutation and other DNA impairments. Although PARP-1 inhibitors have shown clinical success, challenges like acquired resistance and limited efficacy are still matters of concern. Increasing evidence supports the potential of dual-targeting inhibitors that target PARP-1 along with other oncogenic drivers (e.g. HDAC, EGFR, and CDK) to amplify anti-proliferative activity and surmount resistance mechanism. This review comprehensively provides in-depth investigation of dual inhibitors in context to PARP-1, evaluating their design rationale, structure activity relationship (SARs), pharmacological properties, synthetic scheme, and more. By combining mechanistic insights with drug discovery, this work aims to create a road map for generating next-generation PARP-1 inhibitors, providing strategic recommendations in order to improve therapeutic efficacy and broaden clinical applicability across diverse cancer types.

Aim: Novel hybrids of ibuprofen and naproxen were designed as dual COX-2/5-LOX inhibitors to create safer anti-inflammatory drugs.

Materials and methods: The prodrugs were developed through a hybridization molecular approach; their potency against COX-1, COX-2, and 5-LOX was assessed, alongside measurements of PGE2 levels, NO scavenging, and mTOR and Nrf2 protein expression. Molecular docking was used to predict binding interactions.

Results: Hybrids 9 and 10 showed excellent COX-2 inhibition with IC₅₀ values of 3.3 and 2.0 µM, respectively, and high selectivity indices (SI) of 20.7 and 17.2. Both hybrids also demonstrated substantial 5-LOX inhibition with IC₅₀ values of 3.1 and 4.2 µM.

Conclusion: The new hybrids exhibit strong COX-2/5-LOX inhibition, suggesting their structural framework is crucial for developing safer anti-inflammatory drugs.