Novel (thio)barbituric-phenoxy-N-phenylacetamide derivatives as potent urease inhibitors: synthesis,in vitro urease inhibition,and in silico evaluations

Structural Chemistry - A novel series of (thio)barbituric-phenoxy-N-phenylacetamide derivatives 7a-l was synthesized and evaluated against Helicobacter pylori urease. The latter assay revealed that...     

A novel series of thromboxane A2 synthetase inhibitors with free radical scavenging and anti-peroxidative activities

A novel series of indoline derivatives with imidazole and carboxyl moieties were synthesized and evaluated for their thromboxane A2 (TXA2) synthetase inhibiting, radical scavenging and anti-peroxidative activities. Among the compounds synthesized, 3-[5-substituted-3-[2-(imidazol-1-yl)ethyl]indolin-1-yl]propionic acids showed free radical scavenging activity and inhibitory effects on lipid-peroxidation of rat brain homogenate and on arachidonate-induced TXA2-dependent aggregation of rabbit platelets. The anti-platelet and anti-peroxidative activities were related to the lipophilicity of the 5-substituent. The 5-hexyloxy derivative (13) showed about 35-fold higher inhibitory activity on TXA2 synthesis than that of ozagrel and about 100-fold higher activity on lipid peroxidation than that of alpha-tocopherol. Compound 13 showed in vivo anti-thrombotic effect in mice and ex vivo anti-peroxidative activity in rats.     

Identification of novel diclofenac acid and naproxen bearing hydrazones as 15-LOX inhibitors: Design,synthesis, in vitro evaluation,cytotoxicity, and in silico studies

Inflammation is the immune system's adaptive response to tissue dysfunction or homeostatic imbalance, inducing fever, pain, physiological and biochemical changes via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. NSAIDs (non-steroidal anti-inflammatory drugs), such as diclofenac acid and naproxen, are the most common inhibitors of the COX pathway. These drugs, however, are currently being studied as LOX inhibitors as well. Therefore, in the present study, a novel series of diclofenac acid and naproxen-bearing hydrazones 7(a-r) were designed, synthesized, and characterized by different spectroscopic methods like ¹H NMR, ¹³C NMR, IR and HRMS (EI) analysis. All these synthesized compounds were evaluated for their in vitro inhibitory potential against the Soybean 15-lipoxygenase (15-LOX) enzyme. These compounds exhibited varying degrees of inhibitory potential ranging from IC₅₀ 4.61 ± 3.21 μM to 193.62 ± 4.68 μM in comparison to standard inhibitors quercetin (IC₅₀ 4.84 ± 6.43 μM) and baicalein (IC₅₀ 22.46 ± 1.32 μM). The most potent compounds in the series were compounds 7c (IC₅₀ 4.61 ± 3.21 μM), and 7f (IC₅₀ 6.64 ± 4.31 μM). These compounds were found least cytotoxic and showed 96.42 ± 1.3 % and 94.87 ± 1.6 % viability to cells at 0.25 mM concentration respectively. ADME and in silico studies supported the drug-likeness and binding studies of the molecules with the target enzyme.     

Development of non-peptide ACE inhibitors as novel and potent cardiovascular therapeutics: An in silico modelling approach

Angiotensin-converting enzyme (ACE) inhibitors have been acknowledged as first-line agents for the treatment of hypertension and a variety of cardiovascular disorders. In this context, quantitative structure–activity relationship (QSAR) models for a series of non-peptide compounds as ACE inhibitors are developed based on Simplified Molecular Input-Line Entry System (SMILES) notation and local graph invariants. Three random splits into the training and test sets are used. The Monte Carlo method is applied for model development. Molecular docking studies are used for the final assessment of the developed QSAR model and the design of novel inhibitors. The statistical quality of the developed model is good. Molecular fragments responsible for the increase/decrease of the studied activity are calculated. The computer-aided design of new compounds, as potential ACE inhibitors, is presented. The predictive potential of the applied approach is tested, and the robustness of the model is proven using different methods. The results obtained from molecular docking studies are in excellent correlation with the results from QSAR studies. The presented study may be useful in the search for novel cardiovascular therapeutics based on ACE inhibition.     

Design,synthesis and in silico study of pyridine based 1,3,4-oxadiazole embedded hydrazinecarbothioamide derivatives as potent anti-tubercular agent

Development of novel, safe and effective drug candidates combating the emerging drug resistance has remained a major focus in the mainstream of anti-tuberculosis research. Here, we inspired to design and synthesize series of new pyridin-4-yl-1,3,4-oxadiazol-2-yl-thio-ethylidene-hydrazinecarbothioamide derivatives as potential anti-tubercular agents. The anti-tubercular bioactive assay demonstrated that the synthesized compounds exhibit potent anti-tubercular activity (MIC = 3.9–7.81 μg/mL) in comparison with reference drugs Rifampicin and Isoniazid.We employed pharmacophore probing approach for the identification of CYP51 as a possible drug target for the synthesized compounds. To understand the preferable binding mode, the synthesized molecules were docked onto the active site of Sterol 14 α-demethylases (CYP51) target. From the binding free energy of the docking results it was revealed that the compounds were effective CYP51 inhibitors and acts as antitubercular agent.     

Design,synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors

The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms（MPNs）. At present, there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic. In this paper, a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design, synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib. Among them, 21 b exhibited high ...     

Design and synthesis of chitin synthase inhibitors as potent fungicides

Chitin is a structural component of fungal cell walls but is absent in vertebrates,mammals,and humans.Chitin synthase is thus an attractive molecular target for developing fungicides.Based on the structure of its donor substrate,UDP-N-acetyl-glucosamine,as well as the modelled structure of the bacterial chitin synthase NodC,we designed a novel scaffold which was then further optimized into a series of chitin synthase inhibitors.The most potent inhibitor,compound 13,exhibited high chitin synthase inhibitory activity with an IC_(50) value of 64.5 μmol/L All of the inhibitors exhibited antifungal activities against the growth of agriculturally-destructive fungi,Fusarium graminearum,Botrytis cinerea.and Colletotrichum lagenarium.This work presents a new scaffold which can be used for the development of novel fungicides.     

Synthesis,anticancer screening,and in silico ADME prediction of novel 2-pyridones as Pim inhibitors

A novel series of 26 substituted N-(2-ethylphenyl)-2-oxo-pyridine-3-carbonitriles have been designed and synthesized via one-pot synthesis of various aromatic aldehydes, different aromatic acetophenones, and 2-cyano-N-(2-ethylphenyl)acetamide 1 . Moreover, cytotoxicity of the target compounds was evaluated by NCI, which selected 14 compounds for one-dose screening. Among them, compound 21 was selected for five-dose screening, which confirmed its potency against most of cancer cell lines. This compound elicited selectivity profile against human cell line WI-38. Cell cycle analysis was carried out, revealed that compound 21 is an apoptosis inducer causing cell cycle arrest at G2/M. Further exploration on the mode of action by evaluating its effect against Pim-1, Pim-2, and Pim-3 demonstrated its inhibitory effect on Pim-1 and Pim-3 rather than Pim-2. Molecular docking showed that compound 21 binds with high affinity to the active site of Pim-1 enzyme through three hydrogen bonds and two arene-H bonds.     

Combinatorial synthesis of novel and potent inhibitors of NADH:ubiquinone oxidoreductase

BACKGROUND: NADH:ubiquinone oxidoreductase (complex I) is the first of three large enzyme complexes located in the cell's inner mitochondrial membrane which form the electron transport chain that carries electrons from NADH to molecular oxygen during oxidative phosphorylation. There is significant interest in developing small molecule inhibitors of this enzyme for use as biological probes, insecticides and potential chemopreventive/chemotherapeutic agents. Herein we describe the application of novel natural product-like libraries to the discovery of a family of potent benzopyran-based inhibitors. RESULTS: Initially a combinatorial library of benzopyrans, modeled after natural products, was synthesized using a solid phase cycloloading strategy. Screening of this diversity oriented library for inhibitory potency against NADH:ubiquinone oxidoreductase activity in vitro using bovine heart electron transport particles provided several lead compounds which were further refined through a series of focused libraries. CONCLUSIONS: Using this combinatorial library approach, a family of potent 2,2-dimethylbenzopyran-based inhibitors was developed with IC(50) values in the range of 18-55 nM. Cell-based assays revealed that these inhibitors were rather non-cytotoxic in the MCF-7 cell line; however, they were quite cytostatic in a panel of cancer cell lines suggesting their potential as chemotherapeutic/chemopreventive candidates.     

Design,synthesis, biological evaluation and in silico studies of novel 1,2,3-triazole linked benzoxazine-2,4-dione conjugates as potent antimicrobial,antioxidant and anti-inflammatory agents

In an attempt to rationalize the search for new potential anti-inflammatory and anti-infection agents, a new series of 1,4-and 1,5-disubstituted 1,2,3-triazoles linked benzoxazine conjugates have been synthesized via “Click Chemistry” reaction, were designed, synthesized and characterized by means of spectral and elemental data. The newly synthesized compounds have been assessed for their antimicrobial, antioxidant and anti-inflammatory potential. Results revealed that all synthesized compounds display superior activities to the standard drug against different bacterial strains especially S. aureus, M. luteus, and P. aeruginosa, with good to moderate activity towards the tested E. coli bacteria, in respect to the commercial antibiotic, tetracycline. Moreover, the antifungal activity was screened against C. albicans and C. krusei yeasts and results demonstrate potent activity as compared to the standard drug, ampicillin. The antioxidant activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays, whose results indicate that analogues 4a (IC₅₀ 1.88 ± 0.07 µM and 2.17 ± 0.02) followed by 4b (IC₅₀ 2.19 ± 0.09 µM and 2.38 ± 0.43 µM), 4d (IC₅₀ 2.30 ± 0.01 µM and 4.07 ± 0.57 µM), and 4f (2.98 ± 0.02 µM and 3.80 ± 0.01 µM), respectively, exhibited the strongest activity when compared to the standard reference, butylated hydroxytoluene (BHT) (3.52 ± 0.08 µM and 4.64 ± 0.11 µM). In addition, their anti-inflammatory activity was assessed using the xylene-induced ear edema standard technique and the results demonstrated the potency of 4a, 4b and 4d as excellent anti-inflammatory agents. Preliminary structure–activity relationship studies (SARs) provide those biological activities can be modulated by the presence of unsubstituted aromatic ring as well as the position of substituents on the phenyl moiety via electron withdrawing groups (EWGs) or electron donating groups (EDGs) effects. Docking studies on the most promising compounds 4a, 4b, and 4d into the active sites of S. aureus tyrosyl-tRNA synthetase, Candida albicans N-Myristoyltransferase, Human COX-2 enzyme, and Human Peroxiredoxin 5 revealed good binding profiles with the target proteins. The interaction's stability was further assessed using a conventional atomistic 100 ns dynamic simulation study. Hence, our results recommended the rationalized targets 4a, 4b and 4d, to be promising lead candidates for the discovery of novel dual anti-inflammatory and anti-infection agents.     

A quantum chemical study on the free radical scavenging activity of tyrosol and hydroxytyrosol

The free radical scavenging activity of hydroxytyrosol (HTyr) and tyrosol (Tyr) has been studied in aqueous and lipid solutions, using the density functional theory. Four mechanisms of reaction have been considered: single electron transfer (SET), sequential electron proton transfer (SEPT), hydrogen transfer (HT), and radical adduct formation. It was found that while SET and SEPT do not contribute to the overall reactivity of HTyr and Tyr toward ^·OOH and ^·OCH₃ radicals, they can be important for their reactions with ^·OH, ^·OCCl₃, and ^·OOCCl₃. The ^·OOH-scavenging activity of HTyr and Tyr was found to take place exclusively by HT, and it is also predicted to be the main mechanism for their reactions with ^·OCH₃. HT is proposed as the main mechanism for the scavenging activity of HTyr and Tyr when reacting with other ^·OR and ^·OOR radicals, provided that R is an alkyl or an alkenyl group. The major products of reaction are predicted to be the phenoxyl radicals. In addition, Tyr was found to be less efficient than HTyr as free radical scavenger. Moreover, while HTyr is predicted to be a good peroxyl scavenger, Tyr is predicted to be only moderately for that purpose.     

Synthesis,conformational analysis and free radical scavenging activity of some new spiropyranoquinolinones

A series of novel spiroadamantyl- and spirocyclical substituted pyranoquinolin-2-ones were synthesized and the conformation of the pyran ring was investigated. The free radical scavenging activity of the synthesized compounds was determined by their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). All compounds tested scavenged the DPPH radical and among them derivatives possessing extended conjugation showed the highest activity.     

Design,synthesis, and characterization of novel pyrimidines bearing indole as antimicrobial agents

Pyrimidines and pyrimidine bearing indole derivatives are very important species in organic chemistry due to their wide use as bioactive compounds with a broad range of good biological activities. Due to the wide spread of different species of bacteria and fungi nowadays, in the present work, a novel series of indolyl‐pyrimidines (2–13) were synthesized starting from 3‐chloro‐1H‐indole‐2‐carbaldehyde (1) . Elemental analysis, IR, 1H‐NMR, 13C‐NMR, and mass spectral data elucidated the structure of newly synthesized compounds. All compounds were screened for their in vitro antibacterial and antifungal activity, and they demonstrated promising results; all the new compounds synthesized from compound (1) , which allowed reactions with thiourea and ethyl cyanoacetate, gave the target compound (2) , which was used as a precursor for the synthesis of indolylthiazolopyrimidine derivatives (3–8) by reactions with halocarbonyl compounds such as chloroacetone, phancyl bromide, and chloroacetic acid through alkylation of the mercapto group followed by cyclization through a nucleophilic attack. When compound (2) subjected to react with hydrazine hydrate gave 4‐indolyl‐2‐hydrazinopyrimidine (5) , the latter compound, when allowed to react with ethyl chloroacetate or diethyloxalate, gave indolylpyrimidotriazine derivatives (10 , 11) ; in contrast, when the compound reacted with acetic anhydride or formic acid, it gave triazolopyrimidine derivatives (12, 13) .     

Rational design,synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

Heat shock protein 90 (Hsp90) is an appealing anticancer drug target that provoked a tremendous wave of investigations. Geldanamycin (GA) is the first identified Hsp90 inhibitor that exhibited potent anti-cancer activity, but the off-target toxicity associated with the benzoquinone moiety hampered its clinical application. Until now, structure optimization of GA is still in need to fully exploit the therapeutic value of Hsp90. Due to the structural complexity and synthetic challenge of this compound family, conventional optimization is bound to be costly but high efficiency is expected to be reachable by combining the art of rational design and total synthesis. Described in this paper is our first attempt at this approach aiming at rational modification of the C6-position of GA. The binding affinities towards Hsp90 of compound 1 (C6-ethyl) and 2 (C6-methyl) were designed and predicted by using Discovery Studio. These compounds were synthesized and further subjected to a thorough in vitro biological evaluation. We found that compounds 1 and 2 bind to Hsp90 protein with the IC₅₀ of 34.26 nmol/L and 163.7 nmol/L, respectively. Both compounds showed broad-spectrum antitumor effects. Replacing by ethyl, compound 1 exhibited more potent bioactivity than positive control GA, such as in G2/M cell cycle arrest, cell apoptosis and client proteins degradations. The results firstly indicated that the docking study is able to provide a precise prediction of Hsp90 affinities of GA analogues, and the C6 substituent of GA is not erasable without affecting its biological activity.     

Investigation of novel compounds via in silico approaches of EGFR inhibitors as anticancer agents

Before the experimental studies of a compound to be synthesized from in vitro to in vivo, it is possible to save both time and money with in silico approaches only with Computer Aided Drug Design (CADD) methods. In other words, compounds that can be new drug candidates can be suggested by drug design using computational drug discovery strategies. In this study, all molecules in the ChEMBL Database were virtual screened based on drugs with inhibitory properties on the Epidermal Growth Factor Receptor (EGFR), one of the receptor tyrosine kinases, which is effective in cancer cells. During this High-Throughput Screening (HTS), the number of compounds was minimized according to the parameters of the reference drugs, physicochemical properties such as logP, M.W., HBA, HDB, RosLip. As a result of in silico approaches and molecular docking analysis, ten compounds with the highest docking scores were determined and a model compound that could be a new drug candidate was proposed.     

In silico design,synthesis and activity of potential drug-like chrysin scaffold-derived selective EGFR inhibitors as anticancer agents

Background & objectiveEpidermal growth factor receptor (EGFR) signaling pathway is one of the promising and well-established targets for anticancer therapy. The objective of the present study was to identify new EGFR inhibitors using ligand and structure-based drug designing methods, followed by a synthesis of selected inhibitors and evaluation of their activity.MethodsA series of C-7-hydroxyproton substituted chrysin derivatives were virtually drawn to generate a small compound library that was screened using 3D QSAR model created from forty-two known EGFR tyrosine kinase inhibitors. Next, the obtained hits with fitness score ≥ 1.0 were subjected to molecular docking analysis. Based on the predicted activity and XP glide score, three EGFR inhibitors were synthesized and characterized using ¹H-NMR, ¹³C-NMR and MS. Finally, comparative in vitro investigation of the biological activity of synthesized inhibitors was performed with that of the parent molecule, chrysin.ResultsThe data depicted a 3.2–fold enhanced cytotoxicity of chrysin derivative, CHM-04 against breast cancer cells as compared with chrysin as well as its binding with EGFR protein. Furthermore, the biological activity of CHM-04 was comparable to the standard EGFR inhibitor, AG1478 in increasing apoptosis and decreasing the migratory potential of triple-negative breast cancer cells as well as significantly lowering the mammosphere forming ability of breast cancer stem cells.ConclusionThe present study suggests CHM-04, an EGFR inhibitor possessing drug-like properties as a plausible therapeutic candidate against breast cancer.     

Design,in silico,one-pot synthesis,and biological evaluations of novel bis-urea analogs

Research on Chemical Intermediates - The structure of urea has received special attention due to its biological activity. A new and efficient one-pot three-component reaction for the synthesis of...     

Total synthesis of moniliformediquinone and calanquinone A as potent inhibitors for breast cancer

The first synthesis of moniliformediquinone has been achieved in which the longest linear sequence is only nine steps. The synthesis proceeds in 23% overall yield from commercially available 2,4,5-trimethoxybenzaldehyde. The key transformations include a Pd-catalyzed coupling between a phenyl triflate and an acetylene, and a TiCl₄-mediated cyclization of a benzoquinone intermediate. In addition, in vitro inhibitory effects of moniliformediquinone, denbinobin, moscatilin, and calanquinone A were determined to have IC₅₀ values of 0.7, 1.6, 2.5, and 1.5 μM, respectively.