Future medicinal chemistry最新文献

Aim: This research aimed to develop novel indole-2-carboxamides as potential antitubercular agents using rational drug design. It also focused on identifying the critical interactions required for these compounds to exhibit effective antitubercular activity.

Materials and methods: Novel indole-2-carboxamides targeting MmpL3 were designed based on SAR, synthesized, and tested for their antitubercular and iniBAC induction properties. Classical docking and simulated annealing were utilized to understand protein-ligand binding affinity.

Results: Compounds 5c, 5f, and 5i, were active against H37Rv and different MDR and XDR strains of M. tuberculosis. iniBAC promoter induction study indicated that those were inhibitors of MmpL3. Through the docking and simulated annealing studies, we identified key protein-ligand interactions at the MmpL3 binding site.

Conclusion: We have identified three potent antitubercular molecules that supposedly act via inhibiting MmpL3. Results from the molecular modeling studies can be used in future drug designing.

Parkinson's disease (PD) is a common neurodegenerative disease affecting nearly 10 million people worldwide and placing a heavy medical burden on both society and families. However, due to the complexity of its pathological mechanisms, current treatments for PD can only alleviate patients' symptoms. Therefore, novel therapeutic strategies are urgently sought in clinical practice. Leucine-rich repeat kinase 2 (LRRK2) has emerged as a highly promising target for PD therapy. Missense mutations within the structural domain of LRRK2, the most common genetic risk factor for PD, lead to abnormally elevated kinase activity and increase the risk of developing PD. In this article, we provide a comprehensive overview of the structure, biological function, and pathogenic mutations of LRRK2, and examine recent advances in the development of LRRK2 inhibitors. We hope that this article will provide a reference for the design of novel LRRK2 inhibitors based on summarizing the facts and elucidating the viewpoints.

Organoselenium chemistry has become a significant field due to its role in synthesizing numerous biologically active and therapeutic compounds. In early phase, researchers focused on designing organoselenium compounds with antioxidant properties and were quite successful. In last two decades, synthetic chemists shifted their focus toward synthesis of organoselenium compounds with biological properties, moving beyond their traditional antioxidant properties. The review includes synthesis and study of organo-selenium compounds as anticancer, antimicrobial, antiviral, antidiabetic, antithyroid, anti-inflammatory therapies, contributing to disease treatment. This review covers the synthesis and medicinal applications of synthetic organoselenium compounds over the past 10 years, thus making it a valuable resource for researchers in the field of medicinal chemistry.

Background: Poly(ADP-ribose) polymerase (PARP) is a superfamily of enzymes involved in cell survival. Both PARP1 and PARP14 are overexpressed in malignancies. No clinically approved PARP14 inhibitors are available, and PARP1 inhibitors are generally nonspecific, resulting in a need for a more diverse library of selective PARP1 and PARP14 inhibitors.

Materials and methods: Based on the previous lead compounds 1 and 2, 26 novel compounds were designed, synthesized, and screened against PARP1 and PARP14. Compounds with the best in vitro inhibitory results were further screened against PARP2, PARP3, PARP5a, PARP7, and PARP15.

Results and conclusion: The 26 novel compounds demonstrated a lesser inhibitory effect than the lead compounds. Compounds 1 and 2 were further investigated using in vitro cell viability assays, which revealed that cells treated with either lead PARP inhibitor and cisplatin in combination had significantly lower survival rates than those treated with cisplatin alone. At 10 µM, the combination showed more significant cell survival reduction, suggesting greater inhibition of PARP increases lethality, particularly in HeLa and PC-3 cell lines at 96 h and beyond.

Aims: This study aimed to develop novel molecular hybrid conjugates integrating isatin, rhodanine, and phthalimide pharmacophores to create effective analgesic and anti-inflammatory agents with improved safety profiles over existing treatments.

Materials & methods: A series of hybrid conjugates (4a - l) were synthesized and evaluated through in vitro and in vivo biological assays. The most promising compound, 4c, underwent extensive pharmacological and toxicological evaluations. Molecular docking, molecular dynamics simulations, and 2D-QSAR studies were performed to elucidate the mechanism of action and validate the experimental findings.

Results: Compound 4c exhibited potent analgesic and anti-inflammatory activity, effectively inhibiting COX-2 and pro-inflammatory cytokines (IL-6 and TNF-α). Its superior selectivity index (SI) was 1.11 compared to 0.67 for indomethacin. It demonstrated an ulcer index of 2.9 versus 10.23 for indomethacin, indicating reduced gastrointestinal toxicity. Molecular docking simulations revealed a strong binding affinity with COX-2 (-9.832 kcal/mol), and molecular dynamics confirmed the stability of the COX-2 complex.

Conclusions: Compound 4c emerged as a promising lead candidate for developing safer and more effective anti-inflammatory and analgesic agents. Its robust efficacy, safety profile, and computational validation highlight its potential for further optimization in therapeutic applications.

Aim: Benzimidazole-triazole conjugates are very active hotspot for design and synthesis of promising anticancer agents. The target analogs showed potent and selective cytotoxicity over different cancer cell lines for breast and lung ones.

Materials & methods: A new series of bis-1,4-disubstituted-1,2,3-triazoles moieties conjugated with a 2-mercapto-benzimidazole 4a-h and 7a-g was synthesized via the click cycloaddition (CuAAC) reaction. The synthesized triazoles were characterized using several spectroscopic tools. In addition, they were tested against variable cell lines representing different cancer types; HepG-2, MCF-7, HCT-116, and A-549. Computational experiments were introduced for understanding their structure-activity relationships.

Results & conclusion: The data revealed the outperformance of 7a-g analogs over 4a-h one with very effective IC₅₀ values; 4-13 µg/mL compared to the reference drugs. Moreover, detailed mechanistic analyses showed potent Aurora-A Kinase expression for the most active analogs 7a and 7d exhibiting IC₅₀; 3.5 and 5.3 over the control cells 8 ng/mL respectively. Additionally, based on their Aurora-A Kinase inhibitory activity, compound 7a was promising in apoptosis induction and cell cycle arrest. Molecular docking studies with Aurora-A Kinase revealed binding behaviors similar to the co-crystallized ligand sunitinib. Finally, this scaffold exhibits cytotoxic activity via apoptosis, enzyme downregulation, and suppression of cell division.

Aim: Developing new antimicrobial agents in response to the urgent challenge of antimicrobial resistance.

Methods: Synthesis of the targeted coumarins, elucidation of their structures using spectroscopic tools, and investigation of their antimicrobial activity.

Results: Coumarin-pyrazole 11 with CF₃ in the 3-position of the pyrazole ring displayed the lowest minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) with values of 1.95 and 15.6 µg/ml, respectively, against Bacillus pumilis. In addition, it exhibited the best inhibitory activity against Saccharomyces cerevisiae (MIC = 3.91 µg/ml) compared to the rest of the derivatives (7.81-62.5 µg/ml). Surprisingly, coumarin 14 with the S-CH₃ group had higher ability to inhibit the Staphylococcus faecalis strain with an MIC value of 1.95 µg/ml, which is twice that of penicillin G (MIC = 3.91 µg/ml). At the same time, compounds 6, 8, 11, 16, and penicillin G showed similar activity with an MIC value of 3.91 µg/ml against Staphylococcus faecalis. Also, the lowest MIC value (3.91 µg/ml) was obtained for S-CH₃ derivative 14 against Enterobacter cloacae. Coumarins 14 and 1,3,4-thiadiazine derivative 6 recorded the lowest MBC (15.6 µg/ml) against Escherichia coli.

Conclusion: Finally, it can be concluded that some designed coumarins have a high potential to act as potent antimicrobial agents. Some of them displayed higher efficacy than or equal to the reference drug.

Pterostilbene (PT) is a naturally occurring small molecule stilbenoid that has garnered significant attention due to its potential therapeutic effects in tumor diseases. In this review, we conducted a comprehensive analysis of the antitumor effects of PT and its derivatives on various cancer types, including colon, breast, liver, lung, and pancreatic cancers in recent 20 years. We have succinctly summarized the PT derivatives that exhibit superior anti-tumor efficacy compared to PT. Additionally, we reviewed the potential structure-activity relationship (SAR) rules and clinical application methods to establish a foundation for chemical modification and clinical utilization of stilbene compounds.