rifampin and coumarin

A novel series of coumarin-lipoic acid conjugates were synthesized via cycloaddition click reaction to find out new multi-target-directed ligands (MTDLs) for treatment of Alzheimer's disease (AD). All of synthesized compounds were screened for neuroprotective and anti-cholinesterase activities. Based on primary screening, two compounds (5 and 11) were subjected to further biological evaluations. In particular, compound 11 which was the most potent AChE inhibitor showed good inhibitory effect on Aβ-aggregation and intracellular ROS (reactive oxygen species) formation, as well as the ability of selective bio-metal chelation and neuroprotection against H

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Cholinesterase Inhibitors; Cholinesterases; Coumarins; Dose-Response Relationship, Drug; Drug Design; Humans; Hydrogen Peroxide; Ligands; Molecular Docking Simulation; Molecular Structure; PC12 Cells; Protein Aggregates; Rats; Reactive Oxygen Species; Structure-Activity Relationship; Thioctic Acid

Chlamydia trachomatis and Chlamydia pneumoniae are intracellular bacterial pathogens that have been shown to cause, or are strongly associated with, diverse chronic diseases. Persistent infections by both organisms are refractory to antibiotic therapy. The lack of therapeutic efficacy results from the attenuated metabolic rate of persistently infecting chlamydiae in combination with the modest intracellular drug concentrations achievable by normal delivery of antibiotics to the inclusions within which chlamydiae reside in the host cell cytoplasm. In this research, we evaluated whether nanoparticles formulated using the biodegradable poly(d-L-lactide-co-glycolide) (PLGA) polymer can enhance the delivery of antibiotics to the chlamydial inclusion complexes. We initially studied the trafficking of PLGA nanoparticles in Chlamydia-infected cells. We then evaluated nanoparticles for the delivery of antibiotics to the inclusions. Intracellular trafficking studies show that PLGA nanoparticles efficiently concentrate in inclusions in both acutely and persistently infected cells. Further, encapsulation of rifampin and azithromycin antibiotics in PLGA nanoparticles enhanced the effectiveness of the antibiotics in reducing microbial burden. Combination of rifampin and azithromycin was more effective than the individual drugs. Overall, our studies show that PLGA nanoparticles can be effective carriers for targeted delivery of antibiotics to intracellular chlamydial infections.

Topics: Anti-Bacterial Agents; Azithromycin; Cell Line; Chemistry, Pharmaceutical; Chlamydia Infections; Chlamydia trachomatis; Coumarins; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Synergism; Humans; Intracellular Space; Lactic Acid; Microbial Sensitivity Tests; Microbial Viability; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Time Factors

The resurgence of tuberculosis and the emergence of multidrug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We have synthesized a small library of 50 analogues of 4-(arylamino)coumarins with various aromatic amines at the C(4) - position of the coumarin scaffold. The compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37) Rv with rifampicin as the standard. Of the molecules synthesized, compound 9 was found to be most potent with a minimum inhibitory concentration >6.25 μg/mL for 100% inhibition. In an effort to develop new and more effective molecules in this series, the relationship between structure and activity was investigated by comparative molecular field analysis. Various models were generated using comparative molecular field analysis alone and comparative molecular field analysis plus a hydropathy field (HINT). In all, eight models were generated with atom-fit and field-fit alignment strategies. The comparative molecular field analysis models (Models 3a and 4a) based on field-fit alignment were the best with statistically good correlation coefficients (r²) and cross-validated q². The values of r²(pred) for the validation set were 0.469 and 0.516. Based on the comparative molecular field analysis contours, some insights into the structure-activity relationship of the compounds could be gained.

Topics: Antitubercular Agents; Coumarins; Models, Molecular; Mycobacterium tuberculosis; Quantitative Structure-Activity Relationship; Rifampin

A set of 25 coumarin-4-acetic acid benzylidene hydrazides were synthesized and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H(37)Rv strain using the BACTEC 460 system to determine percentage inhibition. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). Several statistically significant CoMFA models were generated. The CoMFA model generated with database alignment was the best in terms of overall statistics. The CoMFA contours provide a good insight into the structure activity relationships of the compounds reported herein.

Topics: Acetic Acid; Antitubercular Agents; Benzaldehydes; Coumarins; Hydrazines; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Quantitative Structure-Activity Relationship