Future medicinal chemistry最新文献

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.

Isoindoline-1,3-dione, also referred as phthalimide, has gained recognition as promising pharmacophore due to the documented biological activities of its derivatives. Phthalimides are a family of synthetic molecules that exhibit notable bioactivity across various fields, particularly as anticancer and anti-inflammatory agents. This review focuses on syntheses and anti-inflammatory studies of the reported phthalimide derivatives. Although there are several synthetic protocols to produce phthalimide derivatives, two methods for synthesizing phthalimides are traditionally used: reacting phthalic anhydride with amines or anilines and the Gabriel synthesis. Due to their structural versatility and established pharmacological effects, derivatives of phthalimides such as the commercially available drugs thalidomide, pomalidomide, and lenalidomide, have driven the development of new derivatives offering hundreds of promising drug candidates with exceptional therapeutic potential, such as LASSBio 468 and adducts 2, 9, 150, 241, 255, and 305 to name some.

Background: Using an analogue-based drug design approach, a number of novel 2-substituted-1,3-thiazolone derivatives (3-10) have been produced and given permission to proceed for their anti-inflammatory properties. In the present paper, the new thiazole derivatives were designed, synthesized, and tested for their alpha-glucosidase, alpha-amylase, and COX-inhibitory activities. Approving the anti-diabetic activity.

Results: All the new derivatives were assessed in vitro compared to control (Acarbose) alpha-glucosidase, and alpha-amylase inhibition influence was showed shown through (3, 5, and 7) that were the most effective compounds as α-glucosidase inhibitors.

Conclusions: Compounds (4 and 7) achieved the best effect as α-amylase inhibitors showed by IC₅₀ score near to that of control (Acarbose). Meanwhile, compound (4) exhibited a lower ferric-reducing anti-oxidant power (FRAP) value when compared to the control experiment (ascorbic acid). A molecular docking study approved the binding affinity and mode of binding of compounds (4 and 5) to the α-glucosidase and α-amylase binding pockets.

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.

Aim: A new series of 3,4-dihydronaphthalen-1(2 h)-ylidene)hydrazineylidene)-5-substituted thiazolidin-4-one derivatives were designed and synthesized.

Results & methodology: The new compounds were screened for in vitro antitumor activity against Hela cancer cell line. The compounds 7b, 7 h, and 7i produced more potent cytotoxicity than doxorubicin with IC₅₀ values of 1.83 ± 0.1, 2.54 ± 0.14, 2.75 ± 0.15, and 3.63 ± 0.2 μM, respectively. They also showed a promising safety profile against WI-38 normal cells. In addition, compound 7b produced a promising multi-kinase inhibition against EGFR (WT) while being very selective toward the mutant forms (L858R and T790M) with IC₅₀ values of 0.099 ± 0.006, 0.064 ± 0.006, and 0.026 ± 0.007 μM, respectively, in comparison to gefitinib and osimertinib. A study of the cell cycle in Hela cells showed that 7b arrests cell cycle in the pre-G1 phase and causes early and late apoptosis. Eventually, the molecular docking results showed that 7b had good-binding interactions with EGFR^WT, EGFR^L858R, and EGFR^T790M.

Conclusion: Compound 7b was predicted to have promising oral absorption, good drug-likeness, and low toxicity risks in humans. Moreover, MD simulations confirmed the stable complexes of 7b with EGFR^WT, EGFRL858R, and EGFR^T790M (with RMSD 0.12-0.35 nm, RMSF 0.2-0.55 nm, SASA 140-150, and Rg 1.80-2.00 nm).

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.

Aim: Emerging resistance among pathogens necessitates the development of novel antimicrobial agents. As a result, we aimed to synthesize new coumarins and study their antimicrobial activity with the hope of obtaining effective drugs.

Method: A series of coumarins were synthesized, characterized, and assessed for antimicrobial activity using broth microdilution and agar diffusion methods against Gram-positive (Bacillus pumilis, Streptococcus faecalis), Gram-negative (Escherichia coli, Enterobacter cloacae) bacteria, and fungi (Saccharomyces cerevisiae, Candida albicans).

Results: Pyrazoles 15 and 16 revealed promising activities against all bacterial strains with MIC values ranging from 1.95 to 15.6 µg/ml. Notably, pyrazole 15 with CF₃ in 3-position of pyrazole ring demonstrated higher ability to inhibit Streptococcus faecalis strain with MIC value equal to penicillin G (3.91 µg/ml). It also exhibited the best bactericidal potency against Escherichia coli with MBC value of 15.6 µg/ml while, pyrazole 16 recorded the same MBC value against Enterobacter cloacae. Pyrazole 15 demonstrated the strongest antifungal activity against both fungal strains with MIC and MFC values of 15.6, 7.81, 62.5, and 31.3 µg/ml against Saccharomyces cerevisiae and Candida albicans, respectively.

Conclusion: These findings underscore the potential of coumarins, particularly compounds 15 and 16, as effective antimicrobial agents and provide critical insights into the design of bioactive molecules.