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.

A new series of pyridazinone derivatives as cholinesterases inhibitors: Synthesis, in vitro activity and molecular modeling studies.

BACKGROUND: The pyridazinone nucleus has been incorporated into a wide variety of therapeutically interesting molecules to transform them into better drugs. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh). Inhibition of cholinesterases is an effective method to curb Alzheimer's disease. Here, we prepared 12 new 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(nonsubstituted/4-substituted benzenesulfonohydrazide) derivatives and evaluated their inhibitory effects on AChE/BChE in pursuit of potent dual inhibitors for Alzheirmer's Disease. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. METHOD: We obtained our compounds by the reaction of various substituted/nonsubstituted benzenesulfonic acid derivatives with 6-substitutedphenyl-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman's method. Molecular docking studies were done using Glide and the results were evaluated on Maestro (Schrödinger, LLC, New York, NY, 2019). RESULTS: The title compounds showed moderate inhibition at 100 µg/ml against both enzymes, yet with better activity against BChE. Compound VI2a emerged as a dual inhibitor with 25.02% and 51.70% inhibition against AChE and BChE, respectively. CONCLUSION: This study supports that novel pyridazinone derivates may be used for the development of new BChE inhibitory agents. It was less potent than the reference drugs, yet promising for further modifications as a lead. The ability of the compounds to adopt energetically more favourable conformations and to engage in more key interactions in the ECBChE active gorge explains their better activity profile against ECBChE.

Synthesis, in-vitro cytotoxic activity and DNA interactions of new dicarboxylatoplatinum(II) complexes with 2-hydroxymethylbenzimidazole as carrier ligands.

OBJECTIVES: The aim of this study was to investigate the in-vitro cytotoxic activity of new platinum(II) complexes on the human HeLa (ER-), MCF-7 (ER+) and MDA-MB 231 (ER-) cell lines. Furthermore, we investigated plasmid DNA interactions and inhibition of BamHI and HindIII restriction enzyme activity of the complex 1-4,7. METHODS: Platinum(II) complexes were synthesised from precursor complexes of [PtL2 Cl2 ] and [PtL2 I2 ]. Their cytotoxic activity was tested by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Their plasmid DNA interactions and restriction enzyme activities were also investigated using the agarose gel electrophoresis method. KEY FINDINGS: The growth inhibitory effect results showed that the cytotoxicity of complex 2 was found to be the most active complex among the synthesised complexes. CONCLUSIONS: The MTT results showed that complex 2 was found to be cytotoxic equal to cisplatin and higher than carboplatin against the MCF-7 and MDA-MB-231 cell lines. Furthermore, the estrogen or progesterone co-treatment slightly increased the cytotoxicity of complex 2, the cisplatin and carboplatin compared with the complex 2 tested alone in 50 µm concentration. According to plasmid DNA interaction and the restriction studies, complexes 1-4,7 modified the tertiary structure of pBR322 plasmid DNA, and complexes 2-4 prevented enzyme digestion at high concentrations.

Cytotoxicity and DNA interactions of some platinum(II) complexes with substituted benzimidazole ligands.

In the present study, four Pt(II) complexes with 2-ethyl (1)/or benzyl (2)/or p-chlorobenzyl (3)/or 2-phenoxymethyl (4) benzimidazole carrier ligands were evaluated for their in vitro cytotoxic activities against the human HeLa cervix, oestrogen receptor-positive MCF-7 breast, and oestrogen receptor-negative MDA-MB 231 breast cancer cell lines. The plasmid DNA interactions and inhibition of the BamHI restriction enzyme activities of the complexes were also studied. Complex 3 was found to be more active than carboplatin for all examined cell lines and comparable with cisplatin, except for the HeLa cell line.

Synthesis of novel 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/-nonsubstituted benzal)hydrazone derivatives and acetylcholinesterase and butyrylcholinesterase inhibitory activities in vitro.

In this study thirteen 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/nonsubstituted benzal)hydrazone V derivatives were synthesized as acetylcholinesterase and butyrylcholinesterase inhibitors. Ten of the synthesized compounds were synthesized for the first time in this study and the rest of them had been synthesized in a previous study. The structures of compounds V were elucidated by IR, 1H-NMR and MASS spectra. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChe) inhibitory activities of V derivatives were measured using Ellman's method. While some of the 6-substituted-3(2H)-pyridazinone-2-propyl-3-(substituted/-nonsubstituted benzal)hydrazone V derivatives exhibited significant AChE inhibitory activity, none of the compoundsshowed BChE inhibitory activity. Theseresults indicate that V derivatives were AChE inhibitors with AChE/ BChE selectivity.

Synthesis, characterization, cytotoxicity, and DNA binding of some new platinum(II) and platinum(IV) complexes with benzimidazole ligands.

In this study, two Pt(II) and three Pt(IV) complexes with the structures of [PtL(2)Cl(2)] (1), [PtL(2)I(2)] (2), [PtL(2)Cl(2)(OH)(2)] (3), [PtL(2)Cl(2)(OCOCH(3))(2)] (4), and [PtL(2)Cl(4)] (5) (L = benzimidazole as carrier ligand) were synthesized and evaluated for their in vitro antiproliferative activities against the human MCF-7, HeLa, and HEp-2 cancer cell lines. The influence of compounds 1-5 on the tertiary structure of DNA was determined by their ability to modify the electrophoretic mobility of the form I and II bands of pBR322 plasmid DNA. The inhibition of BamH1 restriction enzyme activity of compounds 1-5 was also determined. In general, it was found that compounds 1-5 were less active than cisplatin and carboplatin against MCF-7 and HeLa cell lines (except for 1, which was found to be more active than carboplatin against the MCF-7 cell line). Compounds 1 and 3 were found to be significantly more active than cisplatin and carboplatin against the HEp-2 cell line.

3-Chloro-6-{4-[3-(trifluoro-meth-yl)phen-yl]piperazin-1-yl}pyridazine.

The title compound, C(15)H(14)ClF(3)N(4), was synthesized from 3,6-dichloro-pyridazine and 1-[3-(trifluoro-meth-yl)phen-yl]piper-azine. The piperazine ring is flanked by 3-chloro-pyridazine and 3-trifluoro-methyl-phenyl rings and adopts a chair conformation, whereas the 3-chloro-pyridazine and 3-trifluoro-methyl-phenyl rings are planar, with maximum deviations of 0.0069 (13) and 0.0133 (14) Å, respectively. The crystal structure is stabilized by weak inter-molecular C-H⋯N hydrogen-bond inter-actions.

Synthesis and analgesic and anti-inflammatory activities 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted/nonsubstituted benzal)hydrazone derivatives.

In this study new 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzal)hydrazone V derivatives were synthesized as analgesic and anti-inflammatory agents. The structures of compounds were elucidated by spectral and elemental analysis. Compounds Va, Vb and Vc were exhibited more potent analgesic activity than ASA. Also these derivatives demonstrated anti-inflammatory activity as well as standard compound indomethacin. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs). On the basis of available data, the structure-activity relationship of V derivatives was also discussed.

3-Chloro-6-[4-(2-pyrid-yl)piperazin-1-yl]pyridazine.

In the title compound, C(13)H(14)ClN(5), the piperazine ring adopts a chair conformation and the dihedral angle between the aromatic rings is 13.91 (7)°. The crystal structure is stabilized by weak inter-molecular C-H⋯N hydrogen-bond inter-actions.