Synthesis and Evaluation of a New Series of Thiazolyl-pyrazoline Derivatives as Cholinesterase Inhibitors.

OBJECTIVES

In recent years, the design of anticholinesterase agents based on molecular hybridization of pharmacologically active scaffolds has attracted a great deal of interest in medicinal chemistry. For this purpose, we aimed to design and synthesize anticholinesterase agents based on the molecular hybridization of thiazole and pyrazoline scaffolds.

MATERIALS AND

METHODS

New thiazolyl-pyrazoline derivatives were synthesized via the ring closure reaction of 3-(2-furyl)-5-(1,3-benzodioxol-5-yl)-1-thiocarbamoyl-4,5-dihydro-1H-pyrazole with 2-bromo-1-arylethanone derivatives. The compounds were investigated for their inhibitory effects on AChE and BuChE using a modification of Ellman's spectrophotometric method. As a part of this study, the compliance of the compounds to Lipinski's rule of five was evaluated. The physicochemical parameters (log P, TPSA, nrotb, molecular weight, number of hydrogen bond donors and acceptors, molecular volume) were calculated using Molinspiration software.

RESULTS

2-[5-(1,3-Benzodioxol-5-yl)-3-(2-furyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-(naphthalen-2-yl)thiazole was found to be the most effective AChE inhibitor (38.5±2.85%), whereas 2-[5-(1,3-benzodioxol-5-yl)-3-(2-furyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-(4-fluorophenyl)thiazole was found as the most potent BuChE inhibitor (43.02±2.71%) in this series. These compounds only violated one parameter of Lipinski's rule of five. On the basis of Lipinski's rule, they were expected to have reasonable oral bioavailability.

CONCLUSION

In the view of this study, the structural modification of the identified compounds is on-going for the generation of new cholinesterase inhibitors with enhanced efficacy.