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A series of pyridinium salts bearing alkylphenyl groups at 1 position and hydrazone structure at 4 position of the pyridinium ring were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The cholinesterase (ChE) inhibitory activity studies were carried out by using the Ellman's colorimetric method. All compounds displayed considerable AChE and BuChE inhibitory activity and some of the compounds manifested remarkable anti-AChE activity compared to the reference compound, galantamine. Among the title compounds, the series including benzofuran aromatic ring exhibited the best inhibitory activity both on AChE and BuChE enzymes. Key words acetylcholinesterase inhibitor; butyrylcholinesterase inhibitor; docking study; pyridinium salt; hydrazone Acetylcholinesterase (AChE) is an enzyme which is responsible for the hydrolysis of acetylcholine (ACh).1) AChE inhibitors bind to the enzyme thereby increases the level of acetylcholine by inhibiting the hydrolysis of ACh to choline and acetate.2) AChE inhibitors are used as therapeutic agents in the treatment of disorders related to ACh diminution such as Alzheimer disease, myasthenia gravis, glaucoma.3) AChE has a deep, narrow gorge approximately 20 Å long. Catalytic active site (CAS) of the enzyme is located at the bottom of the gorge whereas peripheral anionic site (PAS) is at the entrance. 4) Although anti-AChE drugs show a wide range of chemical diversity, they generally include aromatic-heterocyclic ring systems and a nitrogen atom as chemical structure (Fig. 1). These structures have an important role for the interaction with specific amino acids in the enzyme.5) Aromaticheterocyclic nuclei generally have potential hydrophobic and charge-transfer interaction, while nitrogen atom and its quaternary form can make hydrogen or ionic bonds as well as dipole-dipole or ion-dipole interactions with amino acids in the enzyme gorge.5-10) In addition, quaternary nitrogen cation displays highly positive binding stabilization due to cation-π interactions with amino acid residues in AChE enzyme. [9][10][11][12] Many reports indicated that compounds bearing aromatic/ heteroaromatic rings on lateral parts of pyridinium displayed high AChE inhibitory activity and act as dual binding inhibitors. [13][14][15][16] According to the docking studies of these compounds, it was found that both terminal rings attached to the pyridinium were able to bind simultaneously to both CAS and PAS of the enzyme resulting in higher AChE inhibitory activity. [13][14][15][16] Among the reported studies, pyridinium derivatives having benzofuran ring were shown to have a significant AChE inhibitory activity and it was observed that benzofuran and phenyl moieties as terminal rings were interacted with both PAS and CAS of AChE. 15,16) On the other hand, many of compounds bearing hydrazonehydrazide functional group have been reported to possess ChE inhibitory activity. 17,18) The hydrazones have hydrogen donor and acceptor nitrogen atoms an...

A series of thiazolopyrimidine derivatives was designed and synthesized as a Leishmania major pteridine reductase 1 (LmPTR1) enzyme inhibitor. Their LmPTR1 inhibitor activities were evaluated using the enzyme produced by Escherichia coli in a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro against Leishmania sp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compound L16 exhibited an antileishmanial activity for both the promastigote and amastigote forms of L. tropica, with IC50 values of 7.5 and 2.69 µM, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery.

The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature.

This study was aimed to develop novel compounds to combat antimicrobial resistance, which is one of the biggest threats to global health. For this purpose, compounds bearing triazolopyrimidinone ring and N-(methylnaphthalene)piperazine (NMP) hybrids were designed and synthesized. Ten new compounds were synthesized and after proving their chemical structures were tested for antimicrobial activity using disk diffusion and microdilution method against Gram-negative bacterial strains (Escherichia coli and Pseudomonas aeruginosa), Gram-positive bacterial strains (Staphylococcus aureus and Enterococcus faecalis) and fungal strains (Candida albicans and Candida parapsilosis). Antibiofilm activity and ethidium bromide accumulation assay results were also determined for the selected compounds. Among the tested compounds, hybrid compound H5 showed promising activity against E. faecalis with 16-fold potency compared to its precursor, TP5. Additionally, it has statistically significant inhibition of biofilm production at 10 µg/ml dose against E. coli and P. aeruginosa and a decreasing effect on the relative accumulation of ethidium bromide in P. aeruginosa at 100 µg/ml dose (85.07%) after 30 min. 2,5-disubstitued[1,2,4]triazolo[1,5-a]pyrimidinone heterocyclic core structure and its antimicrobial activity are reported to the literature for the first time in this study.