Investigation of anti- leishmanial activity of the ten different hydrazone derivatives

ULGER, Mahmut/0000-0001-6649-4195WOS: 000378899400006Leishmaniasis is an important parasitic disease in Turkey and the world. Anti-leishmanial drugs such as sodium stibogluconate, miltefosine, paramomycin, amphotericin B, and pentamidine are used for the treatment of leishmaniasis. However, the drugs, used for the chemotheraphy of leishmaniasis, have some side effects such as nephrotoxicity, hepatotoxicity, and teratogenicity. In addition, it is deemed that the discovery and development of the new therapeutic agents must be given priority due to the development of resistance against antimony compounds. The purpose of this study is detecting the anti-leishmanial activity of ten different synthesized hydrazone compounds against Leishmania infantum promastigotes via the microdilution method. The prepared hydrazone compounds, having the concentration of 6 mu g/ml, were added to RPMI-1640 media and the dilution of the hydrazone derivates was performed in the wells of microplates in the range of concentrations of 3 - 0.003 mu g/ml. The microdilution broth method in the microplates was prepared, than the adjusted standard Leishmania infantum promastigotes, 2.5x10(7)cells/mL, were added, into the mentioned microplates which was incubated in 27 degrees C. Twenty h later, the alamar blue were added on the microplates and they were incubated for 4 h. The proliferation of promastigotes was evaluated in 24, 48, and 72 h. It was considered that changing the color from blue to pink in the wells were exhibiting the growth of parasites, while the unchanged color was not. The present study has revealed that the most effective substances against Leishmania infantum promastigotes were 5e, 5g, and 5h compounds (MIC 0.187 mu g/ml) while the least effective compound was 5i (MIC 3 mu g/ml). There is a need for further studies on in vitro activity against the Leishmania amastigotes in macrophages cultures and in vivo experimental animal models for the synthesized compounds showing anti-leishmanial effect in the present study

Synthesis, molecular modelling and biological activity of some pyridazinone derivatives as selective human monoamine oxidase-B inhibitors.

Background: Since brain neurotransmitter levels are associated with the pathology of various neurodegenerative diseases like Parkinson and Alzheimer, monoamineoxidase (MAO) plays a critical role in balancing these neurotransmitters in the brain. MAO isoforms appear as promising drug targets for the development of central nervous system agents. Pyridazinones have a broad array of biological activities. Here, six pyridazinone derivatives were synthesized and their human monoamine oxidase inhibitory activities were evaluated by molecular docking studies, in silico ADME prediction and in vitro biological screening tests. Methods: The compounds were synthesized by the reaction of different piperazine derivatives with 3 (2H)-pyridazinone ring and MAO-inhibitory effects were investigated. Docking studies were conducted with Maestro11.8 software. Results: Most of the synthesized compounds inhibited hMAO-B selectively except compound 4f. Compounds 4a-4e inhibited hMAO-B selectively and reversibly in a competitive mode. Compound 4b was found as the most potent (ki = 0.022 ± 0.001 µM) and selective (SI (Ki hMAO-A/hMAO-B) = 206.82) hMAO-B inhibitor in this series. The results of docking studies were found to be consistent with the results of the in vivo activity studies. Compounds 4a-4e were found to be non-toxic to HepG2 cells at 25 μM concentration. In silico calculations of ADME properties indicated that the compounds have good pharmacokinetic profiles. Conclusion: It was concluded that 4b is possibly recommended as a promising nominee for the design and development of new pyridazinones which can be used in the treatment of neurological diseases

Synthesis and biological evaluation of new 3(2H)-pyridazinone derivatives as non-toxic anti-proliferative compounds against human colon carcinoma HCT116 cells

Novel 3(2H)-pyridazinone derivatives were designed, synthesised in satisfactory yields and evaluated in different experimental assays to assess their preliminary toxicity in vivo and anti-proliferative effects against HCT116 cell lines in vitro. Artemia salina lethality test provided LC50 values >100 µg/mL for all compounds. Successive assays revealed that some compounds were endowed with a promising anti-proliferative effect against HCT116 cells, alone or stimulated by serotonin as a pro-inflammatory factor in order to mimick an inflamed model in vivo of cancer cell microenvironment. Moreover, the kinurenic acid level after treatment with these newly synthesised compounds was monitored as a marker of anti-proliferation in colon carcinoma models. The IC50 values obtained for the best-in-class compounds were comparable to that of daunorubicin as a reference drug. Conversely, these compounds were not able to counteract the spontaneous migration of human cancer HCT116 cell line in the wound healing paradigm