Medicinal Chemistry Research最新文献

Cancers present a significant medical problem despite the development of medical and pharmaceutical sciences leading to a search for further therapeutic approaches. One such approach could involve the use of curcumin or its derivatives. Curcumin reveals interesting antineoplastic effects that could help in the treatment of cancer diseases. However, this natural product possesses some limitations which prevent its application in medicine. Among its limitations, it is characterized by poor water solubility, low stability, and unsatisfactory bioavailability. Aiming to improve the pharmacokinetic properties and enhance the biological effects of curcumin, a series of 30 chemical compounds inspired by its structure was synthesized and characterized. New compounds were subjected to a preliminary MTT viability assessment of 5637 and SCaBER bladder cancer cell lines. Some derivatives revealed the cytotoxic activities already at the concentration of 1 µM. The most active compounds showed no significant acute toxicity in the Microtox test. Intracellular uptake on the basis of the fluorescent properties of the new compounds was analyzed. It was also found that the presence of the morpholine group in the structure improved the biological activity of studied curcumin derivatives. As selected compounds could be considered potential drug candidates, further studies are necessary towards recognition of the exact mechanism of cellular action, the in vivo stability, and toxicity.

A series of 30 derivatives of curcumin was synthesized, characterized and subjected to a MTT viability assessment on 5637 and SCaBER bladder cancer cell lines. Some derivatives revealed the cytotoxic activities at the concentration of 1 µM. Compounds were subjected to acute toxicity study (Microtox test) and intracellular uptake analysis. The presence of the morpholine group in the structure was important for the biological activity of studied derivatives.

Kinetoplastids are a group of flagellated protozoans including medically important parasites of the genus Trypanosoma and Leishmania. The corresponding diseases have afflicted humans for centuries. In an effort to combat kinetoplastid infections, a set of 21 chalcones was synthesized and evaluated for their in vitro anti-protozoal efficacy against Trypanosoma brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania infantum. To ensure safety, these compounds underwent a selectivity evaluation by assessing toxicity against a human lung fibroblast cell line. Compound K4 exhibited remarkable and selective trypanocidal activity against T. b. brucei with IC₅₀ value of 0.31 ± 0.27 µM and T. b. rhodesiense with IC₅₀ value of 0.96 ± 0.86 µM. Compound K9 also showed significant trypanocidal activity against T. b. brucei (IC₅₀: 0.45 ± 0.14 µM) and T. b. rhodesiense (IC₅₀: 0.93 ± 0.51 µM). In both compounds, electron withdrawing groups are appended to the styrenyl moiety.

Pyrimidifen is an excellent commercial acaricide, but it is not low toxic to mammals. Trifluoroethyl thioether derivatives exhibit excellent bioactivity, and flupentiofenox is the first commercially available trifluoroethyl thioether acaricide. To search for novel pesticides, we conducted research around pyrimidifen and flupentiofenox. By introducing trifluoroethyl thioether and F, Cl, CH₃ substituents at different positions on the benzene ring, we successfully introduced trifluoroethyl thioether into the pyrimidine derivatives. Further optimization resulted in compound T7 (HNPC-A188)(5-chloro-6-(difluoromethyl)-N-(2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenoxy)ethyl)pyrimidin-4-amine). HNPC-A188 exhibits excellent acaricidal activity with LC₅₀ values of 0.19 mg/L against Tetranychus urticae, which can be compared with the commercial acaricide cyenopyrafen (LC₅₀ = 0.13 mg/L).

Several new synthesized 4-cinnamamido- and 2-phenoxyacedamido-(1H-pyrazol-5-yl)benzamides were obtained by two multi step different synthetic routes in order to maximize their yield. The new derivatives were screened to determine the antiproliferative, antimicrobial and antibiofilm activity. The biological results showed how, respect to the antiproliferative and antimicrobial activities, the compounds have a low to missing activity. Different are the results obtained concerning the antibiofilm activity, especially towards Candida albicans. Most of the synthesized compounds showed a good percentage inhibition of biofilm formation ranging from 60 to 73% with a Biofilm Inhibition Concentration 50% (BIC₅₀) from 0.13 to 0.01 µM. Among the synthesized compounds the ethyl 5-(4-(2-(4-chlorophenoxy)acetamido)benzamido)-1-methyl-1H-pyrazole-4-carboxylate (27c) resulted the most active molecule with a BIC₅₀ of 0.01 µM. According to the results obtained, such compound could be considered a lead subject of further studies to obtain novel and more effective antibiofilm agents against C. albicans.

A series of novel sulfone derivatives were synthesized and screened in vitro for their cytotoxicity and antifungal activity with annotated primary mechanism of action (MOA). We prioritized sulfones with high (4-(bromodichloromethylsulfonyl)benzoic acid 4, 4-(difluoromethylsulfonyl)benzoic acid 12), little (3-[4-(bromodichloromethylsulfonyl)phenyl]propanoic acid 8, difluoromethyl 4-methylphenyl sulfone 11, 4-(difluoromethylsulfonyl)benzoic acid 12), or no cytotoxicity of 4-(4-(dichloromethylsulfonyl)benzoic acid 3) and 3-[4-(dichloromethylsulfonyl)phenyl]propanoic acid 7 against mammalian cell lines. 3 was found to be the most potent sulfone against Candida albicans (R_log=7.25 at 128–256 µg/mL). The mutation in the CNB1 gene (1) increased the sensitivity of the C. albicans biofilm to 3; (2) reduced ergosterol production and therefore generated higher susceptibility to 4. Sulfone 4 at 128 µg/mL increased cellular RH-123 fluorescence in the wild-type cells of C. albicans, except CNB1/cnb1∆. Moreover, the uptake of sulfones into the cell was unaffected regardless of the presence or absence of RH-123, and the uptake of sulfones was strictly cell/strain dependent. Both RH123 and sulfones cumulatively competed with one another for access to transporters. Calcineurin played a role in this mechanism.

Antimicrobial peptides (AMPs) are naturally occurring molecules that play a vital role in the innate immune responses of various organisms. Additionally, artificial AMPs are also designed based on the common structure-activity relationships (SARs) found in natural ones. As part of our ongoing effort to explore the advantages of each source, this study focused on two representative helical AMPs: Mastoparan C (MPC) and BP52. While the former is derived from the venom of the European wasp Vespa crabro, the latter belongs to a group of artificially designed AMPs inspired by the structure of two natural peptides, Cecropin A and Melittin M. Our data suggests that BP52 exhibits similar antimicrobial activity to MPC but demonstrates significantly higher potency against the A427 cancer cells. Taken together with the shorter length and reduced toxicity to human red blood cells, BP52 exhibited greater potential in drug development compared to its counterpart MPC, thus highlighting the potential of rational design in developing short, potent and selective membrane-active peptides.

In this review, we evaluated the biological activities of hybrid molecules incorporating imidazoles—a cornerstone in medicinal chemistry known for their broad pharmacological spectrum, attributed to the chemical characteristics of their nitrogen atoms. In contrast to earlier reviews, which have concentrated their attention only on a single biological activity that is connected with these hybrid molecules, this review brings together the findings of a variety of investigations that cover a wide range of significant activities including antibacterial, antifungal, antituberculosis, antiviral, anticancer, antioxidant, antidiabetic, anti-inflammatory, and analgesic effects, along with the inhibition of cholinesterase, carbonic anhydrase, and monoamine oxidase (MAO) enzymes. Furthermore, we examined significant pharmacophores such as triazole, thiazole, indole, pyrazole, quinoline, sulfonamide, pyridine, chalcone, coumarin, pyrrole, and pyrrolidine, integrated into imidazole hybrids. Molecular docking studies and structure-activity relationship (SAR) discussions provide insight into the interactions of imidazole hybrids with key enzymes and receptors. This work aspires to contribute valuable insights into the development of novel imidazole hybrids, aiming to address critical health challenges of our era.