Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity.

Azole antifungals, including fluconazole, have long been the first-line antifungal agents in the fight against fungal infections. The emergence of drug-resistant strains and the associated increase in mortality from systemic mycoses has prompted the development of new agents based on azoles. We reported a synthesis of novel monoterpene-containing azoles with high antifungal activity and low cytotoxicity. These hybrids demonstrated broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against both fluconazole-susceptible and fluconazole-resistant strains of Candida spp. Compounds 10a and 10c with cuminyl and pinenyl fragments demonstrated up to 100 times lower MICs than fluconazole against clinical isolates. The results indicated that the monoterpene-containing azoles had much lower MICs against fluconazole-resistant clinical isolates of Candida parapsilosis than their phenyl-containing counterpart. In addition, the compounds did not exhibit cytotoxicity at active concentrations in the MTT assay, indicating potential for further development as antifungal agents.

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.

Azolo[d]pyridazinones in medicinal chemistry.

Azolo[d]pyridazinone is a privileged structure and versatile pharmacophore whose derivatives are associated with diverse biological activities, in particular antidiabetic, antiasthmatic, anticancer, analgesic, anti-inflammatory, antithrombotic, antidepressant and antimicrobial activities. The importance of this scaffold against some targets like PDE, COX and DPP-4 has been reviewed in detail previously. In the present review, we have summarized comprehensive information on azolo[d]pyridazinone derivatives investigated by many researchers for their diverse pharmacological activities, structure-activity relationship and molecular modeling studies since 2000. The review may lead scientists in the research fields of organic synthesis, medicinal chemistry and pharmacology to the strategic design and development of azolo[d]pyridazinone-based drug candidates in the future.

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.