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European Journal of Medicinal Chemistry Mar 20154-Hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme in tyrosine catabolism, is an important target for treating type I tyrosinemia. Inhibition of HPPD can...
4-Hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme in tyrosine catabolism, is an important target for treating type I tyrosinemia. Inhibition of HPPD can effectively alleviate the symptoms of type I tyrosinemia. However, only one commercial HPPD inhibitor, 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione (NTBC), has been available for clinical use so far. In the present study, a series of novel pyrazole-benzimidazolone hybrids were designed, synthesized and evaluated as potent human HPPD inhibitors. Most of the new compounds displayed significant inhibitory activity against the recombinant human HPPD. Moreover, compound 9l was identified as the most potent candidate with IC50 value of 0.021 μM against recombinant human HPPD, about 3-fold more potent than NTBC. Thus the pyrazole-benzimidazolone hybrid has great potential to be further developed for the treatment of type I tyrosinemia.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Benzimidazoles; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 25590863
DOI: 10.1016/j.ejmech.2015.01.018 -
ChemMedChem Sep 2020Small-molecule heterocycles bearing orthogonal functionality have the potential to deliver diverse structural motifs that aid the drug-discovery effort. This work...
Small-molecule heterocycles bearing orthogonal functionality have the potential to deliver diverse structural motifs that aid the drug-discovery effort. This work highlights how a readily assembled N-hydroxyethyl pyrazole trifluoroborate offers rapid access to architecturally distinct 5-6-6- and 5-7-6-fused tricyclic compounds. This chemistry is not only amenable to single compound synthesis, but also to high-throughput experimentation. It gives easy access to diverse compound arrays with various physicochemical and ADME profiles by fully automated library synthesis. The combination of the high-throughput experimentation with rapid testing of the compounds in an integrated physicochemical and ADME profiling workflow allows accelerated design of novel lead compounds in drug-discovery projects.
Topics: Automation; Drug Design; Heterocyclic Compounds; Molecular Structure; Pyrazoles; Small Molecule Libraries
PubMed: 32427423
DOI: 10.1002/cmdc.202000187 -
Bioorganic & Medicinal Chemistry Letters Sep 2021A simple and fast methodology under microwave irradiation for the synthesis of 2-aminopyrimidine and pyrazole derivatives using Atwal reaction is reported. After the...
Synthesis, docking, machine learning and antiproliferative activity of the 6-ferrocene/heterocycle-2-aminopyrimidine and 5-ferrocene-1H-Pyrazole derivatives obtained by microwave-assisted Atwal reaction as potential anticancer agents.
A simple and fast methodology under microwave irradiation for the synthesis of 2-aminopyrimidine and pyrazole derivatives using Atwal reaction is reported. After the optimization of the reaction conditions, eight 2-aminolpyrimidines containing ferrocene and heterocycles and three ferrocene pyrazoles were synthesized from the respective chalcones in good yields. Eight compounds had their structure determined by X-ray diffraction. The molecular hybrid 6a-h and 9a-c were tested on four cancer cell lines - HCT116, PC3, HL60 and SNB19 - where four pyrimidine 6a, 6f-h and one pyrazole 9c derivatives show promising antiproliferative activity. In addition, docking simulation and machine learning methods were carried out to explain the biological activity achieved by the synthetized compounds.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ferrous Compounds; Humans; Machine Learning; Metallocenes; Microwaves; Molecular Docking Simulation; Molecular Structure; Pyrazoles; Pyrimidines; Structure-Activity Relationship
PubMed: 34217828
DOI: 10.1016/j.bmcl.2021.128240 -
Bioorganic & Medicinal Chemistry Letters Dec 2018Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious hospital-acquired infections and is responsible for significant morbidity and mortality in...
Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious hospital-acquired infections and is responsible for significant morbidity and mortality in residential care facilities. New agents against MRSA are needed to combat rising resistance to current antibiotics. We recently reported 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) as a new bacteriostatic agent against MRSA that appears to act via a novel mechanism. Here, twenty nine analogs of HMPC were synthesized, their anti-MRSA structure-activity relationships evaluated and selectivity versus human HKC-8 cells determined. Minimum inhibitory concentrations (MIC) ranged from 0.5 to 64 μg/mL and up to 16-fold selectivity was achieved. The 4-carbodithioate function was found to be essential for activity but non-specific reactivity was ruled out as a contributor to antibacterial action. The study supports further work aimed at elucidating the molecular targets of this interesting new class of anti-MRSA agents.
Topics: Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pyrazoles; Staphylococcus aureus; Structure-Activity Relationship; Thiocarbamates
PubMed: 30297281
DOI: 10.1016/j.bmcl.2018.09.038 -
Bioorganic & Medicinal Chemistry Letters Dec 2011A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a-g) were synthesized and...
A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a-g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC(50) values ranging from 15 to 60 μM. The reference drug pentamidine presented IC(50)=10 μM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.
Topics: Animals; Antiprotozoal Agents; Imidazoles; Leishmania; Leishmaniasis; Mice; Pyrazoles; Structure-Activity Relationship
PubMed: 22055204
DOI: 10.1016/j.bmcl.2011.09.134 -
Journal of Enzyme Inhibition and... Dec 2020In this study, newly synthesised compounds , , and other compounds (, and ) and their inhibitory properties against the human isoforms hCA I and hCA II were reported...
In this study, newly synthesised compounds , , and other compounds (, and ) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds showed effective inhibition profiles with values in the range of 5.13-16.9 nM for hCA I and of 11.77-67.39 nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.
Topics: Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Models, Molecular; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 31797703
DOI: 10.1080/14756366.2019.1695791 -
Molecules (Basel, Switzerland) Sep 2014In order to discover new compounds with good fungicidal activities, 32 pyrazole derivatives were designed and synthesized. The structures of the target compounds were...
In order to discover new compounds with good fungicidal activities, 32 pyrazole derivatives were designed and synthesized. The structures of the target compounds were confirmed by 1H-NMR, 13C-NMR, and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and their fungicidal activities against Botrytis cinerea, Rhizoctonia solani Kuhn, Valsa mali Miyabe et Yamada, Thanatephorus cucumeris (Frank) Donk, Fusarium oxysporum (S-chl) f.sp. cucumerinum Owen, and Fusarium graminearum Schw were tested. The bioassay results indicated that most of the derivatives exhibited considerable antifungal activities, especially compound 26 containing a p-trifluoromethyl- phenyl moiety showed the highest activity, with EC50 values of 2.432, 2.182, 1.787, 1.638, 6.986, and 6.043 μg/mL against B. cinerea, R. solani, V. mali, T. cucumeris, F. oxysporum, and F. graminearum, respectively. Moreover, the activities of compounds such as compounds 27-32 were enhanced by introducing isothiocyanate and carboxamide moieties to the 5-position of the pyrazole ring.
Topics: Antifungal Agents; Fungi; Molecular Structure; Pyrazoles; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship
PubMed: 25203055
DOI: 10.3390/molecules190914036 -
Molecular Diversity Feb 2011One-pot synthesis of different benzochromeno-pyrazole derivatives has been reported via reaction of aldehydes, 3-methyl-1H-pyrazol-5(4H)-one and α-naphthol/β-naphthol...
One-pot synthesis of different benzochromeno-pyrazole derivatives has been reported via reaction of aldehydes, 3-methyl-1H-pyrazol-5(4H)-one and α-naphthol/β-naphthol in the presence of sulfamic acid.
Topics: Aldehydes; Benzopyrans; Pyrazoles; Sulfonic Acids
PubMed: 20683770
DOI: 10.1007/s11030-010-9263-4 -
Organic & Biomolecular Chemistry Aug 20133-(4-Chlorophenyl)-4-substituted pyrazole derivatives were synthesised and tested for their in vitro antifungal activity. Some compounds showed very good antifungal...
3-(4-Chlorophenyl)-4-substituted pyrazole derivatives were synthesised and tested for their in vitro antifungal activity. Some compounds showed very good antifungal activity against four pathogenic strains of fungi. The same compounds exhibited an interesting activity against the tested strain of Mycobacterium tuberculosis H37Rv. The results suggest that 1,3,4-oxadiazoles and 5-pyrazolinones bearing a core pyrazole scaffold may be promising antifungal and antitubercular agents.
Topics: Antifungal Agents; Aspergillus; Candida; Cryptococcus neoformans; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Pyrazoles; Structure-Activity Relationship
PubMed: 23779132
DOI: 10.1039/c3ob27290g -
Nucleosides, Nucleotides & Nucleic Acids 2019This study reports a novel and efficient method for the synthesis of the first reported novel class of pyrazole thioglycosides 6a-h. These series of compounds were...
This study reports a novel and efficient method for the synthesis of the first reported novel class of pyrazole thioglycosides 6a-h. These series of compounds were designed through the reaction of sodium 2-cyano-3-oxo-3-(4-substitutedphenylamino)prop-1-ene-1,1-bis(thiolate) salts 2 with hydrazine hydrate in ethanol at room temperature to give the corresponding sodium 5-amino-4-(substitutedphenylcarbamoyl)-1H-pyrazole-3-thiolates 3a-d. The latter compounds were treated with protected α-D-gluco- and galacto-pyranosyl bromides 4a,b in DMF at ambient temperature to give in a high yields the corresponding pyrazole thioglycosides 6a-h. Treatment of pyrazole salts 3a-d with hydrochloric acid at amobient temperature afforded the corresponding 3-mercaptopyrazole derivatives 5. The latter compounds were treated with peracetylated sugars 4 in sodium hydride in ethanol at ambient temperature to tolerate the S-glycosyl 6a-h compounds. Ammonolysis of the pyrazole thioglycosides 6a-h afforded the corresponding free thioglycosides 7a-h. The toxicity and antitumor activities of the synthesized compounds were studied.
Topics: Amides; Animals; Antioxidants; Drug Design; Male; Mice; Molecular Structure; Pyrazoles; Ribonucleosides; Ribose; Structure-Activity Relationship; Thioglycosides
PubMed: 30961430
DOI: 10.1080/15257770.2018.1508693