Design, synthesis, and bioactivity evaluation of clindamycin derivatives against multidrug-resistant bacterial strains.

Our research aims to reduce the bacterial resistance of clindamycin against Gram-positive bacteria and expand its range of bacterial susceptibility. First, we optimized the structure of clindamycin based on its structure-activity relationship. Second, we employed the fractional inhibitory concentration method to detect drugs suitable for combination with clindamycin derivatives. We then used a linker to connect the clindamycin derivatives with the identified combined therapy drugs. Finally, we tested antibacterial susceptibility testing and conducted in vitro bacterial inhibition activity assays to determine the compounds. with the highest efficacy. The results of our study show that we synthesized clindamycin propionate derivatives and clindamycin homo/heterodimer derivatives, which exhibited superior antibacterial activity compared to clindamycin and other antibiotics against both bacteria and fungi. In vitro bacteriostatic activity testing against four types of Gram-negative bacteria and one type of fungi revealed that all synthesized compounds had bacteriostatic effects at least 1000 times better than clindamycin and sulfonamides. The minimum inhibitory concentration (MIC) values for these compounds ranged from 0.25 to 0.0325 mM. Significantly, compound 5a demonstrated the most potent inhibitory activity against three distinct bacterial strains, displaying MIC values spanning from 0.0625 to 0.0325 mM. Furthermore, our calculations indicate that compound 5a is safe for cellular use. In conclusion, the synthesized compounds hold great promise in addressing bacterial antibiotic resistance.

Clindamycin Derivatives: Unveiling New Prospects as Potential Antitumor Agents.

This study delves into the exploration of Clindamycin derivatives, specifically compounds 3 and 3e, to unveil their antitumor potential by employing a multidisciplinary approach. Screening a repertoire of 200 Clindamycin-associated targets pinpointed the Family A G-protein-coupled receptor as a prominent antitumor candidate. Subsequent analyses unearthed 16 pertinent antitumor proteins, with compound 3 exhibiting robust affinity towards a specific protein via stable hydrogen bonding. Molecular dynamics simulations underscored the adrenergic receptor ß as a pivotal target, primarily situated in the plasma membrane and endoplasmic reticulum. These revelations hint towards compound 3's potential to bolster natural defense mechanisms against tumors by modulating immune responses within the tumor microenvironment, thus paving the way for novel avenues in antitumor drug development. Furthermore, employing the MTT assay, we evaluated the anti-HepG2 cell activity of compounds 3 and 3e, with 5-fluorouracil serving as the control drug. Results revealed that compound 3 exhibited significant differences (p < 0.01) across all concentrations (2.5, 5, 10 µg/mL) compared to the control group, paralleled by the pronounced differences (p < 0.01) observed with 5-fluorouracil.

Structure-Activity Relationship Target Prediction Studies of Clindamycin Derivatives with Broad-Spectrum Bacteriostatic Antibacterial Properties.

This study investigated the potential of clindamycin derivatives with broad-spectrum antibacterial properties. The main goal was to identify new antibacterial targets to lay the foundation for developing novel antimicrobial agents. This research used molecular docking and dynamics simulations to explore how clindamycin derivatives could combat bacterial resistance and widen their antibacterial capabilities. Three different clindamycin derivatives were studied against 300 target proteins. Among these, 26 proteins were found to be common targets for all three derivatives. After further screening through molecular docking and dynamics simulations, four specific protein targets were identified. Notably, one of these targets, cell division protein FtsZ, was found to be primarily located in the cyto and cyto_nucl compartments. These findings suggest that clindamycin derivatives have the potential to address bacterial resistance and broaden their antibacterial effectiveness through these identified protein targets.

Potential therapeutic target for polysaccharide inhibition of colon cancer progression.

In recent years, colon cancer has become one of the most common malignant tumors worldwide, posing a great threat to human health. Studies have shown that natural polysaccharides have rich biological activities and medicinal value, such as anti-inflammatory, anti-cancer, anti-oxidation, and immune-enhancing effects, especially with potential anti-colon cancer mechanisms. Natural polysaccharides can not only protect and enhance the homeostasis of the intestinal environment but also exert a direct inhibition effect on cancer cells, making it a promising strategy for treating colon cancer. Preliminary clinical experiments have demonstrated that oral administration of low and high doses of citrus pectin polysaccharides can reduce tumor volume in mice by 38% (p < 0.02) and 70% (p < 0.001), respectively. These results are encouraging. However, there are relatively few clinical studies on the effectiveness of polysaccharide therapy for colon cancer, and ensuring the effective bioavailability of polysaccharides in the body remains a challenge. In this article, we elucidate the impact of the physicochemical factors of polysaccharides on their anticancer effects and then reveal the anti-tumor effects and mechanisms of natural polysaccharides on colon cancer. Finally, we emphasize the challenges of using polysaccharides in the treatment of colon cancer and discuss future applications.

Losmapimod Protected Epileptic Rats From Hippocampal Neuron Damage Through Inhibition of the MAPK Pathway.

Objective: This research aimed to validate the therapeutic effect of losmapimod and explore the underlying mechanism in its treatment of epilepsy. Methods: A rat model of epilepsy was constructed with an injection of pilocarpine. Microarray analysis was performed to screen aberrantly expressed mRNAs and activated signaling pathways between epileptic rats and normal controls. A TdT-mediated dUTP nick-end labeling (TUNEL) assay was used to identify cell apoptosis. Hippocampal cytoarchitecture was visualized with Nissl staining. The secretion of inflammatory factors as well as the marker proteins in the mitogen-activated protein kinase (MAPK) pathway were detected by Western blot. A Morris water maze navigation test evaluated the rats' cognitive functions. Results: Activation of the MAPK signaling pathway was observed in epilepsy rats. A decrease in the MAPK phosphorylation level by application of losmapimod protected against epilepsy by reducing neuron loss. Losmapimod effectively improved memory, reduced the frequency of seizures, protected the neuron from damage, and limited the apoptosis of neurons in epilepsy rats. Conclusion: The application of losmapimod could partly reverse the development of epilepsy.