86404-63-9Relevant academic research and scientific papers
Design, synthesis and antitrypanosomal activity of some nitrofurazone 1,2,4-triazolic bioisosteric analogues
Silva, Fredson T.,Franco, Caio H.,Favaro, Denize C.,Freitas-Junior, Lucio H.,Moraes, Carolina B.,Ferreira, Elizabeth I.
, p. 553 - 560 (2016)
Chagas disease, caused by Trypanosoma cruzi, is a parasitosis that predominates in Latin America. It is estimated that 25 million people are under the risk of infection and, in 2008, more than 10 thousand deaths were registered. The only two drugs available in the therapeutics, nifurtimox and benznidazole, showed to be more effective in the acute phase of the disease. However, there is no standard treatment protocol effective for the chronic phase. Nitrofurazone (NF), an antimicrobial drug, has activity against T. cruzi, although being toxic. Considering the need for new antichagasic drugs, the existence of promising new therapeutic targets, as 14α-sterol demethylase and cruzain, and employing the bioisosterism and molecular hybridization approaches, four novel compounds were synthesized, characterized by melting point range, elemental analysis, IR and NMR spectroscopy. The compounds were tested against T. cruzi amastigotes in infected U2OS cells. All compounds showed selectivity towards T. cruzi and showed trypanomicidal activity in low micromolar range. The compound 3 showed potency similar to benznidazole, but lower efficacy. These results highlight the importance of the 1,2,4-triazole, thiosemicarbazonic and nitro group moieties for designing new efficient compounds, potentially for the chronic phase of Chagas disease.
Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections
Xu, Hang,Yan, Zhong-zuo,Guo, Meng-bi,An, Ran,Wang, Xin,Zhang, Rui,Mou, Yan-hua,Hou, Zhuang,Guo, Chun
, (2021/03/16)
A series of selenium-containing miconazole derivatives were identified as potent antifungal drugs in our previous study. Representative compound A03 (MIC = 0.01 μg/mL against C.alb. 5314) proved efficacious in inhibiting the growth of fungal pathogens. However, further study showed lead compound A03 exhibited potential hemolysis, significant cytotoxic effect and unfavorable metabolic stability and was therefore modified to overcome these drawbacks. In this article, the further optimization of selenium-containing miconazole derivatives resulted in the discovery of similarly potent compound B17 (MIC = 0.02 μg/mL against C.alb. 5314), exhibiting a superior pharmacological profile with decreased rate of metabolism, cytotoxic effect and hemolysis. Furthermore, compound B17 showed fungicidal activity against Candida albicans and significant effects on the treatment of resistant Candida albicans infections. Meanwhile, compound B17 not only could reduce the ergosterol biosynthesis pathway by inhibiting CYP51, but also inhibited biofilm formation. More importantly, compound B17 also shows promising in vivo efficacy after intraperitoneal injection and the PK study of compound B17 was evaluated. In addition, molecular docking studies provide a model for the interaction between the compound B17 and the CYP51 protein. Overall, we believe that these selenium-containing miconazole compounds can be further developed for the potential treatment of fungal infections.
Antibacterial drug and preparation method thereof
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, (2020/06/20)
The invention discloses an antibacterial drug. The antibacterial drug is 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(1H-1,2,3,4-tetrazol-1-yl)-2-propanol, the compound is obtained by modifyingfluconazole and introducing a tetrazole ring. Compared with fluconazole, the compound has wider antimicrobial activity spectrum. The invention also discloses a preparation method of the antibacterialdrug. The method comprises the step of introducing the tetrazole ring to obtain 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(1H-1,2,3,4-tetrazol-1-yl)-2-propanol on the basis of retaining moststructures with drug effects on fluconazole.
Synthesis, optimization, antifungal activity, selectivity, and cyp51 binding of new 2-aryl-3-azolyl-1-indolyl-propan-2-ols
Lebouvier, Nicolas,Pagniez, Fabrice,Na, Young Min,Shi, Da,Pinson, Patricia,Marchivie, Mathieu,Guillon, Jean,Hakki, Tarek,Bernhardt, Rita,Yee, Sook Wah,Simons, Claire,Lézé, Marie-Pierre,Hartmann, Rolf W.,Mularoni, Angélique,Le Baut, Guillaume,Krimm, Isabelle,Abagyan, Ruben,Pape, Patrice Le,Borgne, Marc Le
, p. 1 - 32 (2020/08/17)
A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key intermediate 1-(1H-benzotriazol-1-yl)methyl-1H-indole and the final opening of oxiranes by imidazole or 1H-1,2,4-triazole. The second route allowed access to the target compounds in only three steps, this time with the ring opening by indole and analogs. Twenty azole derivatives were tested against Candida albicans and other Candida species. The enantiomers of the best anti-Candida compound, 2-(2,4-dichlorophenyl)-3-(1H-indol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (8g), were analyzed by X-ray diffraction to determine their absolute configuration. The (?)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC80 = 0.000256 μg/mL on C. albicans CA98001) was found with the S-absolute configuration. In contrast the (+)-8g enantiomer was found with the R-absolute configuration (MIC = 0.023 μg/mL on C. albicans CA98001). By comparison, the MIC value for FLC was determined as 0.020 μg/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure of Candida albicans lanosterol 14α-demethylase (CaCYP51). The (?)-(S)-8g enantiomer aligned with the positioning of posaconazole within both the heme and access channel binding sites, which was consistent with its biological results. All target compounds have been also studied against human fetal lung fibroblast (MRC-5) cells. Finally, the selectivity of four compounds on a panel of human P450-dependent enzymes (CYP19, CYP17, CYP26A1, CYP11B1, and CYP11B2) was investigated.
Preparation method of 2' 4'-difluoro-2-[1-(1H-1, 2, 4-triazolyl)] acetophenone
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Paragraph 0028; 0035-0036, (2020/08/27)
The invention provides a preparation method of 2' 4'-difluoro-2-[1-(1H-1, 2, 4-triazolyl)] acetophenone. 2-chloro-2' 4'-difluoroacetophenone serving as a raw material reacts with 3-chloro-1, 2, 4-triazole to obtain 2-(3-chloro-1H-1, 2, 4-triazolyl-1-(2, 4-difluorophenyl) ethanone, and then palladium-on-carbon hydrogenation dehalogenation is carried out to obtain a final product 2' 4'-difluoro-2-[1-(1H-1, 2, 4-triazolyl) acetophenone. The method for preparing 2' 4'-difluoro-2-[1-(1H-1, 2, 4-triazolyl)] acetophenone is simple in steps, convenient to operate, low in economic cost, suitable for industrial production, capable of bringing good social benefits and economic benefits and large in economic value potential.
Voriconazole and intermediate preparation method
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Paragraph 0013; 0030-0041, (2019/05/15)
The present invention discloses a Voriconazole condensate isomer as raw materials for recovery under acidic conditions to obtain 4 - chloro - 6 - ethyl - 5 - fluoro pyrimidine and 2 '4' - difluoro - 2 - [1 - (1 H - 1, 2, 4 - triazolyl)] acetophenone, and can further be used for the preparation of Voriconazole. The method can greatly improve the prior art for preparing the utilization rate of the fu likang zuozuo original auxiliary materials, the cost is reduced.
Novel carbazole-triazole conjugates as DNA-targeting membrane active potentiators against clinical isolated fungi
Zhang, Yuan,Tangadanchu, Vijai Kumar Reddy,Bheemanaboina, Rammohan R. Yadav,Cheng, Yu,Zhou, Cheng-He
, p. 579 - 589 (2018/06/20)
A series of carbazole-triazole conjugates were designed, synthesized and characterized by IR, NMR, and HRMS spectra. Biological assay showed that most of the synthesized compounds exhibited moderate and even strong antifungal activities, especially 3,6-dibromocarbazolyl triazole 5d displayed excellent inhibitory efficacy against most of the tested fungal strains (MIC = 2–32 μg/mL) and effectively fungicidal ability towards C. albicans, C. tropicals and C. parapsilosis ATCC 22019 (MFC = 4–8 μg/mL). Its combination use with fluconazole could enhance the antifungal efficacy, and compound 5d also did not obviously trigger the development of resistance in C. albicans even after 10 passages. Preliminary mechanism study revealed that the active molecule 5d could depolarize fungal membrane potential and intercalate into DNA to possibly block DNA replication, thus possibly exhibiting its powerful antifungal abilities. Conjugate 5d could interact with HSA, which was constructive for the further design, modification and screening of drug molecules. Docking investigation demonstrated a non-covalent binding of 5d with CYP51 through hydrogen bond and hydrophobicity. These results strongly suggested that compound 5d could act as a potential template for the development of promising antifungal drugs.
Triazole compound and application of triazole compound serving as fungicide
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Paragraph 0023; 0025; 0026, (2018/06/28)
The invention relates to a triazole compound with a general formula (I). In the general formula (I), X is selected from substituting groups including H, C1 to C4 linear-chain or branched-chain alkyl,halogen, nitryl, cyano, phenyl, trifluoromethyl, trichloromethyl, methoxyl and the like and the quantity is 1 to 3. (The formula (I) is shown in the description.) The compound shown as the general formula (I) is used as fungicide and can be used for preventing and controlling banded sclerotial blight, anthracnose, rape sclerotinia rot, watermelon wilt disease, wheat scab, phyricularia oryzae, tomato early blight, phytophthora capsici leonian, banana leaf spot disease, rice false smut, wheat rust, pear tree scab, apple tree altermaria leaf spot and powdery mildew. The compound synthesized by the invention has a novel structure, has higher or equivalent fungicidal activity on certain pathogenic fungi when being compared with commercial fungicide and has a relatively high commercial prospect.
Preparation method of voriconazole intermediate
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Paragraph 0041; 0042; 0044; 0046; 0048; 0050; 0052; 0054, (2018/04/03)
The invention discloses a preparation method of a voriconazole intermediate. The preparation method comprises the following steps of firstly, preparing 2,4-difluoro brmorobenzene (compound 2) into a format reagent; then reacting with 4-(2-chloracetyl)morpholine (compound 4), so as to obtain a compound, namely 2'-chloro-2,4-difluoroacetophenone (compound 5); finally, enabling the compound 5 to react with 1,2,4-sodium triazole, so as to obtain the voriconazole intermediate (compound 1). The preparation method has the advantages that the cost of the raw materials is low, and the obtaining is easy; the reaction conditions are moderate, the requirement on a reaction kettle is low, and the good industrialization prospect is realized.
Discovery of potential antifungal triazoles: Design, synthesis, biological evaluation, and preliminary antifungal mechanism exploration
Zhang, Yuan,Damu, Guri L. V.,Cui, Sheng-Feng,Mi, Jia-Li,Tangadanchu, Vijai Kumar Reddy,Zhou, Cheng-He
, p. 1631 - 1639 (2017/08/22)
A series of triazoles as miconazole analogues was designed, synthesized and characterized by IR, NMR, MS and HRMS. All the newly prepared compounds were screened for their antifungal activities against five kinds of fungi. The bioactive assay showed that most of the synthesized compounds exhibited good or even stronger antifungal activities in comparison with the reference drugs miconazole and fluconazole. In particular, the 3,4-dichlorobenzyl derivative 5b showed a comparable or superior activity against all the tested fungal strains to standard drugs, and formed a supramolecular complex with CYP51 via the hydrogen bond between the 4-nitrogen of the triazole nucleus and the histidine residue. Preliminary experiments revealed that both of the active molecules 5b and 9c could intercalate into calf thymus DNAs, which might block DNA replication to exhibit their powerful antifungal abilities. Further studies indicated that compound 5b might be stored and transported by human serum albumin through hydrophobic interactions, specific electrostatic interactions and hydrogen bonds. These results strongly suggested that compound 5b could serve as a promising antifungal candidate.
