Synthesis and Tyrosinase Inhibitory Activity of Novel Benzimidazole/Thiazolidin-4-one Hybrid Derivatives.

In this study, novel 3-(phenylamino)thiazolidin-4-one 2 a-d and 3-(phenyl)thiazolidin-4-one 3 a-g derivatives which are having benzimidazole moiety were synthesized and their tyrosinase inhibitory activity were investigated. The structures of the target compounds were elucidated using 1 H/13 C-NMR, IR and MS. The structure of 2 b was also characterized using HSQC NMR technique. Among the target compounds, 3 b-g demonstrated stronger tyrosinase inhibitory activity (IC50 values for 3 b-g ranged from 80.93 to 119.20 µM), compared to the positive control kojic acid (IC50 : 125.08 µM). With IC50 value of 80.93 µM, 5-(2-(4-(1H-benzimidazol-1-yl)phenyl)-4-oxothiazolidin-3-yl)-2-methylbenzenesulfonamide 3 g was found to be the most active derivative of the series. Molecular docking studies were conducted to elucidate the binding interactions between compounds and tyrosinase. The MTT assay studies used to determine the cytotoxicity of 3 b-g showed that 3 c, 3 d, 3 f and 3 g were not cytotoxic in the range of 0-200 µM. Considering its tyrosinase inhibitory activity and cytotoxic effect, 3 g exhibits promising potential for further research and development as a novel tyrosinase inhibitor.

Design, Synthesis and Cytotoxic Evaluation of N-Acylhydrazone-Incorporated Isoxazolo[4,5-d]pyridazin-4(5H)-one Derivatives.

A series of isoxazolo[4,5-d]pyridazin-4(5H)-one hybrids with N-acylhydrazone structure was prepared and screened for their cytotoxic activities. The in vitro antiproliferative activity of the target molecules was evaluated against a panel of sixty cancer cell lines (NCI-60) by the National Cancer Institute. Seven of the target compounds showed prominent % inhibition against various cancer cell lines at the one-dose assay and were subsequently screened for five-dose assay. 4d, 4e and 4g (full panel mean graph midpoint GI50 =9.33, 5.25 and 7.94 µM) emerged as the most promising derivatives against multiple cancer cell lines in comparison with 5-fluorouracil and gefitinib (full panel mean graph midpoint GI50 =18.60 and 3.46 µM). They exhibited remarkable antiproliferative activity with GI50 values submicromolar concentrations against some of the cell lines. The compounds were also found to display mild toxicity to the healthy cells compared to the cancer cell lines indicating safety. Druglikeness and high oral bioavailability were predicted for most of the compounds. As a result, a current study unveiled isoxazolo[4,5-d]pyridazin-4(5H)-ones bearing N-acylhydrazone as promising anticancer agents with antiproliferative effects.

Design and synthesis of new 2-oxoquinoxalinyl-1,2,4-triazoles as antitumor VEGFR-2 inhibitors.

VEGFR-2 is a tyrosine kinase receptor for VEGFs that play a central role in tumor angiogenesis. The inhibition of the tyrosine kinase domain of VEGFR-2 has become an attractive therapeutic strategy in recent years for inhibiting tumor growth. In this study, a series of novel 2-oxoquinoxalinyl-1,2,4-triazoles were designed and synthesized as potential antitumor agents and VEGFR-2 inhibitors. Eight compounds in this series showed high growth inhibition against MCF-7 with GI50 ranging from 1.6 to 8.06 µM compared to staurosporine (GI50 = 8.39 µM) and sorafenib (GI50 = 11.20 µM). In addition, the results of the in vitro tyrosine kinase inhibition of VEGFR-2 revealed that most of the compounds possessed IC50 values in the sub-micromolar range. Compound 6g (IC50 = 0.037 µM) showed more potent VEGFR-2 inhibitory activity than sorafenib (IC50 = 0.045 µM). Furthermore, docking studies of the compounds with tyrosine kinase domain of VEGFR-2 (PDB ID: 4ASD) were performed. According to the results, 6g exhibited hydrogen bonding interactions with Glu885, Asp1046 and Cys919 amino acids in a similar way to sorafenib. Finally, physicochemical predictions of target compounds were examined in silico. The results revealed that all the compounds possessed promising drug-likeness profile.

Insights into the chemistry and therapeutic potential of acrylonitrile derivatives.

Acrylonitrile is a fascinating scaffold widely found in many natural products, drugs, and drug candidates with various biological activities. Several drug molecules such as entacapone, rilpivirine, teriflunomide, and so forth, bearing an acrylonitrile moiety have been marketed. In this review, diverse synthetic strategies for constructing desired acrylonitriles are discussed, and the different biological activities and medicinal significance of various acrylonitrile derivatives are critically evaluated. The information gathered is expected to provide rational guidance for the development of clinically useful agents from acrylonitriles.

Novel benzimidazole-acrylonitrile hybrids and their derivatives: Design, synthesis and antimycobacterial activity.

This paper reports the synthesis and evaluation of some benzimidazole-acrylonitrile hybrid derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. Among the derivatives studied, 3b was found to be the most active compound with MIC of 0.78 µg/mL against M. tuberculosis. This is a quite good activity compared with ethambutol (MIC = 1.56 µg/mL). Moreover, 3b showed 2.8 log fold reduction in bacterial count of dormant forms of mycobacterium which is more potent than first line drugs isoniazid, ciprofloxacin, rifampicin and moxifloxacin. Having activities against both active and dormant forms of M. tuberculosis,3b may be a useful candidate for the development of new drugs to treat tuberculosis.

Synthesis, molecular docking, and biological evaluation of novel 2-pyrazoline derivatives as multifunctional agents for the treatment of Alzheimer's disease.

A novel series of 2-pyrazoline derivatives were designed, synthesized, and evaluated for cholinesterase (ChE) inhibitory, Aß anti-aggregating and neuroprotective activities. Among these, 3d, 3e, 3g, and 3h were established as the most potent and selective BChE inhibitors (IC50 = 0.5-3.9 µM), while 3f presented dual inhibitory activity against BChE and AChE (IC50 = 6.0 and 6.5 µM, respectively). Kinetic analyses revealed that 3g is a partial noncompetitive inhibitor of BChE (Ki = 2.22 µM), while 3f exerts competitive inhibition on AChE (Ki = 0.63 µM). The active compounds were subsequently screened for further assessments. 3f, 3g and 3h reduced Aß1-42 aggregation levels significantly (72.6, 83.4 and 63.4%, respectively). In addition, 3f demonstrated outstanding neuroprotective effects against Aß1-42-induced and H2O2-induced cell toxicity (95.6 and 93.6%, respectively). Molecular docking studies were performed with 3g and 3f to investigate binding interactions inside the active sites of BChE and AChE. Compounds 3g and 3f might have the multifunctional potential for use against Alzheimer's disease.

Some New Hydrazone Derivatives Bearing the 1,2,4-Triazole Moiety as Potential Antimycobacterial Agents.

OBJECTIVES: The aim of this study was to synthesize, characterize, and screen some new 1-(4-((2-(4-substitutedphenyl)hydrazono)methyl)phenyl)-1H-1,2,4-triazole derivatives for their antimycobacterial activities. MATERIALS AND METHODS: The target compounds (2a-h) were gained by condensation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde with appropriate phenylhydrazines. Their structures were elucidated by IR, 1H-NMR, and mass spectrometry. The antimycobacterial activities of the compounds were determined in vitro against Mycobacterium tuberculosis H37Rv. RESULTS: The biological assay results showed that the methylsulfonyl-substituted derivative 2f displayed the highest antimycobacterial activity in this series. CONCLUSION: Although the methylsulfonyl-substituted derivative exhibited significant antimycobacterial activity, none of the synthesized compounds was as effective as isoniazid, rifampin, ethambutol, and ciprofloxacin against M. tuberculosis.

Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles.

The present study describes the synthesis, pharmacological evaluation (BChE/AChE inhibition, Aß antiaggregation, and neuroprotective effects), and molecular modeling studies of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives. The alkyl-substituted derivatives exhibited selective inhibition on BChE with varying efficiency. Compounds 3b and 3d were found to be the most potent inhibitors of BChE with IC50 values of 5.18 and 5.22µM, respectively. The kinetic studies revealed that 3b is a partial non-competitive BChE inhibitor. Molecular modeling studies also showed that the alkyl-substituted derivatives were able to reach the catalytic anionic site of the BChE. The compounds with an inhibitory effect on BChE were subsequently screened for their Aß antiaggregating and neuroprotective activities. Compounds 3a and 3b exerted a potential neuroprotective effect against H2O2 and Aß-induced cytotoxicity in SH-SY5Y cells. Collectively, 3b was found as the most promising compound for the development of multi-target directed ligands against Alzheimer's disease.

Novel Thiazolidinone-Azole Hybrids: Design, Synthesis and Antimycobacterial Activity Studies.

To develop novel antimycobacterial agents, a new series of thiazolidinone-azole hybrids 4a-b, 5a-b and 6-13 were designed and synthesized. Thiazolidin-4-ones (4a-b and 5a-b) were obtained by the reaction of Schiff bases and hydrazones (2a-b and 3a-b) with mercaptoacetic acid. 5-Benzylidene derivatives (6-13) were gained by treatment of 5a-b with appropriate benzaldehydes according to Knoevenagel condensation. To evaluate their structures 1H NMR, IR, mass spectrometry and elemental analysis data were used. The target compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv strain using the microplate alamar blue assay method. Among them, 6, 10 and 12 (MIC: 14.27-14.74 µM) were found as most active compounds in the series. It was seen that both phenylamino and benzylidene substitutions on thiazolidin-4-one ring caused an improvement in the antimycobacterial activity.

Novel thiazolo[3,2-b]-1,2,4-triazoles derived from naproxen with analgesic/anti-inflammatory properties: Synthesis, biological evaluation and molecular modeling studies.

3-Substituted-1,2,4-triazole-5-thiones are versatile synthetic intermediates for the preparation of several biologically active N-bridged heterocyclic compounds, given that they have two reactive sites, thiocarbonyl and an amine nitrogen (N1/N4). For several years, our interest has focused on the synthesis of novel heterocyclic systems derived from 3-substituted-1,2,4-triazole-5-thiones having analgesic/anti-inflammatory activity. In this study, a series of novel thiazolo[3,2-b]-1,2,4-triazole-6(5H)-one derivatives bearing naproxen was synthesized and evaluated for their in vivo analgesic and anti-inflammatory properties in acute experimental pain and inflammation models. The compounds were also tested for their ulcerogenic potential. Our findings showed that all the newly synthesized derivatives attenuate nociception and inflammation compared with a control. All the synthesized compounds exhibited much lower ulcerogenic risk than the standard drugs indomethacin and naproxen. Some compounds with significant analgesic and/or anti-inflammatory activities as well as low ulcer scores were further evaluated for in vitro COX-1 and COX-2 inhibitory potential in a COX-catalyzed prostaglandin biosynthesis assay. Among the tested compounds, compound 1q showed the highest selectivity index (SI) of 4.87. The binding mode for some of the tested compounds to the cyclooxygenase (COX) enzymes was predicted using docking studies.

Design, synthesis and in vitro study of 5,6-diaryl-1,2,4-triazine-3-ylthioacetate derivatives as COX-2 and ß-amyloid aggregation inhibitors.

In order to find novel cyclooxygenase (COX)-2 inhibitors for treating inflammatory-based diseases such as Alzheimer's disease (AD), an ethyl carboxylate side chain was added to 5-(4-chlorophenyl)-6-(4-(methylsulfonyl)phenyl)-3-(methylthio)-1,2,4-triazine (lead compound II) to maintain residual inhibition of COX-1 through interacting with Arg120. A preliminary molecular docking study on both the COX-1/COX-2 active sites truly confirmed our hypothesis. Accordingly, a series of ethyl 5,6-diaryl-1,2,4-triazine-3-ylthioacetate derivatives were synthesized and their chemical structures were confirmed by NMR, IR and MS spectra. Further in vitro COX-1/COX-2 evaluations revealed that compound 6c (COX-2 IC50 = 10.1 µM, COX-1 IC50 = 88.8 µM) is the most selective COX-2 inhibitor while maintaining residual inhibition of COX-1. In order to evaluate their potential use against AD, an in vitro evaluation of ß-amyloid fibril formation was performed. The results indicated that the prototype compounds 6 are effective ß-amyloid destabilizing agents while compound 6c could inhibit 94% of the ß-amyloid fibril formation after 48 h. Finally, the in silico assessment results of their blood-brain barrier permeability were satisfactory.

1,2-Diaryl-2-hydroxyiminoethanones as dual COX-1 and ß-amyloid aggregation inhibitors: biological evaluation and in silico study.

To find out new agents for treating inflammatory-involved diseases such as Alzheimer's disease, a series of 1,2-diaryl-2-hydroxyiminoethanones containing vicinal diaryl pharmacophore of COX inhibitors were tested by a set of in vitro, in vivo, and computational studies. The in vivo study of compounds indicated their prominent anti-inflammatory ability at the doses of 10 and 20 mg/kg comparable to celecoxib (10 mg/kg). Further in vitro COX-1/COX-2 evaluations revealed that 4-methoxy derivative 3 had a high selective COX-1 inhibitory activity (COX-1, IC50=0.12 µm, SI>833). To evaluate their potential use against Alzheimer's disease, in vitro evaluation of ß-amyloid fibril formation using Aß(1-40) and Aß(1-42) peptides was performed. The evaluation of their antiaggregation ability gave impressive results and comparable to rifampicin and indomethacin. Conformational study of compound 3 and subsequent docking of its restrained analogs on both active sites of COX-1 and COX-2 could provide a proof of its COX-1 selectivity as well as molecular dynamic simulation could elucidate and give more insight into the amyloid disaggregation mechanisms leading to rational design of inhibitors.

Biological activity and molecular docking studies of curcumin-related α,ß-unsaturated carbonyl-based synthetic compounds as anticancer agents and mushroom tyrosinase inhibitors.

Hyperpigmentation in human skin and enzymatic browning in fruits, which are caused by tyrosinase enzyme, are not desirable. Investigations in the discovery of tyrosinase enzyme inhibitors and search for improved cytotoxic agents continue to be an important line in drug discovery and development. In present work, a new series of 30 compounds bearing α,ß-unsaturated carbonyl moiety was designed and synthesized following curcumin as model. All compounds were evaluated for their effects on human cancer cell lines and mushroom tyrosinase enzyme. Moreover, the structure-activity relationships of these compounds are also explained. Molecular modeling studies of these new compounds were carried out to explore interactions with tyrosinase enzyme. Synthetic curcumin-like compounds (2a-b) were identified as potent anticancer agents with 81-82% cytotoxicity. Five of these newly synthesized compounds (1a, 8a-b, 10a-b) emerged to be the potent inhibitors of mushroom tyrosinase, providing further insight into designing compounds useful in fields of food, health, and agriculture.

Molecular modeling, synthesis and screening of some new 4-thiazolidinone derivatives with promising selective COX-2 inhibitory activity.

In order to develop new selective cyclooxygenase-2 inhibitors, a series of novel 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones were designed. Molecular modeling studies with COX-2 enzyme were performed by using MOE program. The designed compounds with reasonable binding modes and high docking scores were synthesized. Their COX-1/COX-2 inhibitory activities were evaluated in vitro, using NS-398 and indomethacine as reference compounds. Compounds possessing methyl group (3d and 4d) on the phenyl ring exhibited highly COX-2 inhibitory selectivity and potency.

Synthesis and cyclooxygenase inhibitory activities of some N-acylhydrazone derivatives of isoxazolo[4,5-d]pyridazin-4(5H)-ones.

In this study, new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives having an N-acylhydrazone moiety were synthesized. The compounds were tested for their COX inhibitory activities using NS-398 and indomethacine as reference compounds. Although the compounds had an inhibitory profile against both COX-1 and COX-2, most were found to be more selective against COX-2 by a small percentage of inhibition, at the concentration of 50 microM. Docking studies were done to understand the interactions of the tested compounds with the active site of COX-2. It was observed that the compounds fit into, and interacted with, the hydrophobic parts which are common in the active pocket of COX-1 and COX-2 enzymes but could not fit to the area which is specific for COX-2 enzyme.