No abstract

The development of efficacious and safe drugs for the treatment of neurological diseases related to glutamate toxicity has been a focus in neuropharmacological research. Specifically, discovering antagonists to modulate the activity and kinetics of AMPA receptors, which are the fastest ligand-gated ion channels involved in excitatory neurotransmission in response to glutamate. Thus, the current study investigated novel curcumin derivatives on the biophysical properties of AMPA receptors, specifically on the homomeric GluA2 and the heteromeric GluA2/A3 subunits and assessed for inhibitory actions. The biophysical parameter (i.e., desensitization, deactivation, and peak currents) were measured by using whole-cell patch clamp electrophysiology with and without the administration of the derivatives onto HEK293 cells. CR-NN, CR-NNPh, CR-MeNH, and CR-NO of the tested derivatives showed inhibition on all AMPA receptors up to 6 folds. Moreover, the inhibitory derivatives also increased desensitization and deactivation, which further intensifies the compounds’ neuroprotective effects. However, CR-PhCl, CR-PhF, and CR-PhBr did not show any significant changes on the peak current, deactivation or desensitization rates. By comparison to other discovered and widely used antagonist, the prepared curcumin derivatives are not selective to a specific AMPA subunit, instead implement its effect in the same way between all types of AMPA receptors. Additionally, the obtained results provide derivatives that not only noncompetitively inhibit AMPARs but also decrease its biophysical kinetics, specifically desensitization and deactivation rates. Hence, to potentially serve as a new AMPAR inhibitor with therapeutic potential, the current study provides compounds that are non-selective and non-competitive antagonist, which also effect the desensitization and deactivation rates of the receptor.

Background: Curcumin is a safe, versatile natural product with unlimited number of biological activities and a precursor for various heterocyclic compounds. Objective: Present study was aimed to development of a curcumin based antimicrobial reagent with high potency against gram-positive and gram-negative bacteria. Methods: Herein we report a simple and convenient one step method for synthesizing a series of 1,4-benzodiazepines via condensation cyclization reaction between curcumin and various 1,2-phenylenediamine in refluxed ethanol. Results: A series of new 1,4-benzodiazepins were synthesized and their structures were supported by FT-IR, 1H NMR, 13C NMR, and mass spectral analysis. Synthesized 1,4-benzodiazepins were evaluated for their in vitro antimicrobial activity against gram positive (S. aureus and S. epidermidis) and gram negative (E. coli and P. aeruginosa) bacteria. They exhibited low to high potency against the tested organisms. In particular, dichlorinated 1,4-benzodiazepine 9 exhibited a remarkable potency against the gram-positive bacteria S. aureus (MIC: 3.125 μg mL−1, MBC: 12 μg mL−1). It showed a higher potency than most of the tested reference drugs. Compound 9, showed medium activity against E. Coli. Genotoxic study revealed that, benzodiazepines 9 attacked the the DNA of E. Coli strains and damaged it. The potency of compound 9, could be attributed to the multiple chlorine atoms present on the aromatic ring. Conclusion: Some of the synthesized curcumin based benzodiazepines showed excellent potency against gram positive bacteria. These benzodiazepines could be a great candidate as a future antimicrobial agent.