Fragment-Based Drug Design and Drug Repositioning Using Multiple Ligand Simultaneous Docking (MLSD): Identifying Celecoxib and Template Compounds as Novel Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3) (original) (raw)
Related papers
SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL PYRAZOLE DERIVATIVES
Pyrazoles are chemical compounds that contain a five membered heterocyclic with two nitrogen atoms and three head-to-head carbons. Pyrazole derivatives, some members of the pyrazoles class, have presented excellent pharmacological effectiveness and biological antimicrobial [1] ,anti-inflammatory [2] , antihistaminic [3] , antiviral [4] , Anticonvulsant [5] , fungicidal activities [6] , herbicidal [7-8] , antitumor, cytotoxic [9] , and antiviral [10-11] , activities. Pyrazole derivatives also act as antiangiogenic agents [12] , A3 adenosine receptor antagonists [13] , neuropeptide YY5 receptor antagonists [14] , kinase inhibitor for treatment of type 2 diabetes, hyperlipidemia, obesity [15] , and thrombopiotinmimetics [16] , here in we report the synthesis of novel pyrazole derivatives and their antimicrobial activities. METERIAL AND METHODS Melting points of compounds were determined in open capillary tubes using Veego melting point apparatus and are uncorrected. Purity of compounds was monitored by TLC on silica F 254 coated aluminum plates (Merck) as adsorbent and U.V. light. IR spectra (KBr in cm-1) were recorded on a Shimadzu Model FTIR-435. NMR spectra were recorded on a Varian Mercury TH-400 operating at 400 MHz (1 H NMR) and 100 MHz (13 C NMR) using CDCl 3 as a solvent and TMS as an internal standard (Chemical shift in ppm). All chemicals and solvents used are of analytical grade. EXPERIMENTAL SECTION Synthesis of (Z)-ethyl 4-(3-(trifluoromethyl)phenyl)-4hydroxy-2-oxobut-3-enoate 2. To a mixture of 1-(3-(trifluoromethyl)phenyl)ethanone1 (0.10 mol) and diethyl oxalate (0.15 mol) in 50mL of anhydrous toluene was added sodium hydride (60 %) (0.2 mol). The resulting mixture was stirred at 35-40°C for 7 hr; the solvent was evaporated under vacuum, the crude mixture was poured in 100 mL of ice cold water and acidified by dilute hydrochloric acid. Solid precipitated obtained was filtered and washed with water. Solid compound was dried under vacuum at 50°C. The crude product was purified by crystallization in methanol.
Scientific Reports, 2023
Pyranopyrazole derivatives have a vital role in the class of organic compounds because of their broad spectrum of biological and pharmacological importance. Our current goal is the [3 + 3] cycloaddition of benzoyl isothiocyanate and pyrazolone 1 to undergo oxidation cyclization, producing pyrazoloxadiazine 3. The diol 5 was obtained as a condensation of two equivalents of 1 with thiophene-2-carboxaldehyde in acetic acid above the sodium acetate mixture. When the condensation was carried out in piperidine under fusion, unsaturated ketone 4 was obtained. The pyrazolo pyran derivative 11 resulted from the [3 + 3] cycloaddition of 1 and cinnamic acid, while the Pyrone derivative was prepared by acylation of 12 with two equivalents of acetic anhydride. Phthalic anhydride undergoes arylation using zinc chloride as a catalyst. The cyclic keto acid 23 was synthesized by the action of succinic anhydride on 12 in the acetic medium, while the latter reacted with cinnamic acid, leading to pyrazole derivative 24. All of these reactions were through the Michael reaction mechanism. All the tested compounds showed good antimicrobial activity against pathogenic microorganisms; newly synthesized compounds were also screened for their antioxidant activity. Rational studies were carried out by the ABTs method to allow a broader choice of activities. In addition, similar offcompounds were conducted. Molecular docking studies with the CB-Dock server and MD simulations were created with the default settings of the Solution Builder on the CHARMM-GUI server at 150 nm. A good correlation was obtained between the experimental results and the theoretical bioavailability predictions using POM theory.
Journal of Molecular Structure, 2018
In the present study, a series of novel and biologically potent 6-amino-1-(2,4-dinitrophenyl)-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile derivatives (5a-5u) have been synthesized through multicomponent reaction between various substituted aromatic aldehyde derivative (4a-4u), 2, 4-dinitrophenyl hydrazine (1), ethyl acetoacetate (2) and malononitrile (3) in the presence of SnCl 2 as a prompt catalyst using both microwave irradiation method as well as conventional method. The structure of synthesized compounds were confirmed by various spectroscopic methods such as 1 H-NMR, 13 C-NMR, IR, Mass analysis and elemental analysis. All the synthesized compounds were subjected in vitro antibacterial, antituberculosis screening and cytotoxicity MTT assay. In vitro biological study revealed that the synthesized compound 5a, 7a and 8a are showing good anti-bacterial and anti-tuberculosis activity. The in silico study of ADME pharmacokinetic properties were also predicted for synthesized compounds for checking their bioavailability. Furthermore, molecular docking study of synthesized compounds with enoyl-ACP reductase (oxidoreductase) was carry out to find out the binding affinity of compounds. Docking study demonstrated that compound 7b and 7a possessed superior binding affinity with target enzyme by strong hydrogen bonding. We have also carried out molecular dynamics simulation to check the stability of docked complex, conformational changes and primary molecular interaction.
European Journal of Medicinal Chemistry, 2010
Several novel molecules, 1-(3 0 -(9H-carbazol-4-yloxy)-2 0 -hydroxypropyl)-3-aryl-1H-pyrazole-5-carboxylic acid derivatives 3aeg were synthesized and screened to evaluate their cytotoxicity against cancer cells in vitro. The compounds 3aeg has been prepared by the reaction of ethyl 3-aryl-1H-pyrazole-5carboxylate with 4-oxiranylmethoxy-9H-carbazole in moderate to excellent yields. The cytotoxicity of synthesized compounds was evaluated by a SRB (sulforhodamine B) assay against cancer cell such as SKeNeSH human neuroblastoma (NB), human A549 lung carcinoma, human breast cancer MCF-7 cell lines. The results showed that seven compounds can suppress SKeNeSH tumor cancer cell growth. Among them, compound 3d was the most effective small molecule in inhibiting SKeNeSH cell growth.
Journal of Molecular Structure
A new series of 2-(4-((5-(4-bromophenyl)-1, 3, 4-oxadiazol-2-yl)methoxy)phenyl)-1H-benzo[de] isoquinoline-1,3(2H)-dione derivatives (6a-l) have been synthesized by using conventional method. All the newly synthesized compounds were evaluated for their antibacterial and antifungal activity four bacterial strains S. aureus, E. coli, B. subtilis, and P. aeruginosa. Ciprofloxacin used standard drug. The antifungal activity screened against two pathogenic fungal strains A.niger and C. albicans and Voriconazole used as standard drug. The antibacterial results shows that compounds 6i more than 6f are as potent against S. aureus with compare to standard drug. In the case of B. subtilis the compounds 6f more than 6i are more active. In the case of E.coli the compounds 6i more than 6f are more active. The compounds 6f and 6i are more active against P. aeruginosa. The anti-fungal activity result shows that the compounds 6f and 6i are as active as standard drug Voriconazole against A.niger. In the case of C. albicans the compounds 6f and 6i are showing the same activity with compare to standard drug. All the synthesized novel compounds were characterized by FTIR, 1 H-NMR, 13 C-NMR, HRMS spectroscopic methods and the elemental analysis (C, H and N).
European Journal of Medicinal Chemistry, 2010
Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the deactivation of fatty acid ethanolamides such as the endogenous cannabinoid anandamide, the intestinal satiety factor oleoylethanolamide, and the peripheral analgesic and antiinflammatory factor palmitoylethanolamide. In the present study, we report on the design, synthesis, and structure-activity relationships (SAR) of a novel class of potent, selective, and systemically active inhibitors of FAAH activity, which we have recently shown to exert potent anxiolytic-like effects in rats. These compounds are characterized by a carbamic template substituted with alkyl or aryl groups at their O-and N-termini. Most compounds inhibit FAAH, but not several other serine hydrolases, with potencies that depend on the size and shape of the substituents. Initial SAR investigations suggested that the requirements for optimal potency are a lipophilic N-alkyl substituent (such as n-butyl or cyclohexyl) and a bent O-aryl substituent. Furthermore, the carbamic group is essential for activity. A 3D-QSAR analysis on the alkylcarbamic acid aryl esters showed that the size and shape of the O-aryl moiety are correlated with FAAH inhibitory potency. A CoMSIA model was constructed, indicating that whereas the steric occupation of an area corresponding to the meta position of an O-phenyl ring improves potency, a region of low steric tolerance on the enzyme active site exists corresponding to the para position of the same ring. The bent shape of the O-aryl moieties that best fit the enzyme surface closely resembles the folded conformations observed in the complexes of unsaturated fatty acids with different proteins. URB524 (N-cyclohexylcarbamic acid biphenyl-3-yl ester, 9g) is the most potent compound of the series (IC 50 ) 63 nM) and was therefore selected for further optimization.
ALCHEMY Jurnal Penelitian Kimia, 2021
Breast cancer is a disease in which cells in the breast tissue change and divide in an uncontrolled way. Pyrazoline is a promising agent reported against cancer. In this work, we have synthesized pyrazoline 4-(3-(2-chlorophenyl)-5-(2-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamide (EMP-1). The reaction was successfully carried out in one-pot three components from 2-chloroacetophenone, 2-methoxybenzaldehyde, and 4-hydrazinylbenzenesulfonamide as starting materials. The reaction was conducted by assisting the irradiation of Monowave 50 (Anton-Paar) with a high yield of 91%. Its potential anti-breast cancer was investigated by molecular docking and dynamic studies. The molecular docking study showed that EMP-1 had binding energy of -7.17 kcal/mol. The spatial arrangement of EMP-1 was similar to the positive control of doxorubicin. These results indicate that EMP-1 compound potentially developed as anti-breast cancer.
ACS Medicinal Chemistry Letters
The amide (1.5 eq.), Pd2(dba)3 (5 mol%), XantPhos (10 mol%), cesium carbonate (3 eq.) and the 2chloropyridinylimidazole derivative (1 eq.) were dissolved under an atmosphere of argon in DMF (0.3 M). The reaction mixture was then stirred at 100 °C for 16 h. The reaction mixture was allowed to cool to rt and sat. aq. NH4Cl solution was added. It was extracted with EtOAc (3x) and the combined organic layers were washed with sat. aq. NH4Cl solution (2x) and brine. After drying over anhydrous Na2SO4 the solvent was removed under reduced pressure and the compound was purified by flash chromatography.
Russian Journal of Bioorganic Chemistry, 2019
Objective: The main objective of this work was to design, synthesize and evaluate the novel pyrazoline incorporated 1,2,3-triazole benzene sulphonamides for cytotoxic and anti-gout activities also to perform Insilco molecular docking studies. Methods: Designed compounds were synthesized by condensation of different substituted chalcones (3a-i) with hydrazine hydrate and substituted phenylhydrazines. All the synthesized compounds were characterized on the basis of physical and spectral data. To predict the affinity and activity of the ligand molecule Libdock program was employed to generate different bioactive binding poses of designing molecules at the active site of protein Phosphatidylinositol 3-kinase (PI3Kα). Title compounds were evaluated for cytotoxic activity by using 3-(4, 5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay and anti-gout activity by potassium oxonate induced assay. Results: All the synthesized compounds showed characteristic peaks in FTIR, 1 H, 13 C NMR and MASS spectral analysis. In molecular docking studies, compound 3i has shown good binding affinity to the active site of PI3Kα with a docking score of 145.031 and 4 hydrogen bonding interactions with least hepatotoxicity and good bioavailability when compared with that of reference ligand KKR exhibited a Libdock score of 88.35. Remaining compounds also have a good binding affinity with a minimum of 2 bonding interactions and having better absorption, distribution, metabolism, elimination and toxicity (ADMET) profile. The same compound (3i) exhibited the highest cytotoxic activity with an IC50 value of 4.54µg/ml. Compound 4d was evaluated for anti-inflammatory activity and it has significantly ameliorated against potassium oxonate induced gout in mice when compared with that of standard drug allopurinol due to its anti-inflammatory property. Conclusion: We designed and synthesized a novel series of title compounds in quantitative yields and performed docking studies. New derivatives have a good binding affinity towards PI3Kα enzyme, good bioavailability, least hepatotoxicity and significant cytotoxic activity.
International Journal of Pharmacy and Pharmaceutical Sciences, 2019
Objective: The main objective of this work was to design, synthesize and evaluate the novel pyrazoline incorporated 1,2,3-triazole benzene sulphonamides for cytotoxic and anti-gout activities also to perform Insilco molecular docking studies. Methods: Designed compounds were synthesized by condensation of different substituted chalcones (3a-i) with hydrazine hydrate and substituted phenylhydrazines. All the synthesized compounds were characterized on the basis of physical and spectral data. To predict the affinity and activity of the ligand molecule Libdock program was employed to generate different bioactive binding poses of designing molecules at the active site of protein Phosphatidylinositol 3-kinase (PI3Kα). Title compounds were evaluated for cytotoxic activity by using 3-(4, 5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay and anti-gout activity by potassium oxonate induced assay. Results: All the synthesized compounds showed characteristic peaks in FTIR, 1 H, 13 C NMR and MASS spectral analysis. In molecular docking studies, compound 3i has shown good binding affinity to the active site of PI3Kα with a docking score of 145.031 and 4 hydrogen bonding interactions with least hepatotoxicity and good bioavailability when compared with that of reference ligand KKR exhibited a Libdock score of 88.35. Remaining compounds also have a good binding affinity with a minimum of 2 bonding interactions and having better absorption, distribution, metabolism, elimination and toxicity (ADMET) profile. The same compound (3i) exhibited the highest cytotoxic activity with an IC50 value of 4.54µg/ml. Compound 4d was evaluated for anti-inflammatory activity and it has significantly ameliorated against potassium oxonate induced gout in mice when compared with that of standard drug allopurinol due to its anti-inflammatory property. Conclusion: We designed and synthesized a novel series of title compounds in quantitative yields and performed docking studies. New derivatives have a good binding affinity towards PI3Kα enzyme, good bioavailability, least hepatotoxicity and significant cytotoxic activity.