Synthesis of some new hydrazone derivatives containing sulfonate moieties and investigation of their biological activities

In this thesis, the synthesis of two distinct series of new hydrazone derivatives (2a–f and 3a–f) was carried out, and their inhibitory activities against human carbonic anhydrase isoenzymes I and II (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) targets were investigated. These interactions were detailed using both in vitro assays and in silico methods. It was observed that all synthesized compounds exhibited inhibition in the nanomolar range, with IC₅₀ values calculated in the ranges of 47.3–317.8 nM for hCA I, 71.9–376.2 nM for hCA II, 81.01–832.9 nM for AChE, and 134.5–2264 nM for BChE. Upon comparison of the activity results, it was determined that derivatives coded 2a and 2b, in particular, exerted a more potent inhibitory effect on the hCA I isoenzyme than the reference drug acetazolamide (AZA). Another noteworthy finding is that all synthesized molecules displayed a higher efficacy profile on AChE compared to rivastigmine. In this group, compound 2f, in particular, emerged as the strongest candidate for AChE inhibition. In the comparison specific to the BChE enzyme, it was determined that certain specific derivatives (2b, 2c, 2f, 3a, and 3b) achieved superior nanomolar inhibition values compared to rivastigmine. Within the framework of a multi-target approach, compound 2b was concluded to be the most suitable inhibitor candidate for all three enzymes: hCA I, hCA II, and BChE. Furthermore, the B3LYP-D3BJ/6-311++G(d,p) methodology was utilized in the thesis to elucidate the electronic structures of the molecules and to ensure their geometric optimizations. Molecular docking and molecular dynamics simulations were applied to determine the probable binding positions of the ligands and their interaction dynamics with the receptor. In the final stage, the pharmacokinetic behaviors, ADME parameters, and toxicological profiles of the prominent compounds 2b and 2f were evaluated via the SwissADME and ADMETlab 3.0 platforms.