Design, synthesis and antifungal activity of novel triazole derivatives

Twenty-three 1 -(1H-1,2,4-triazole-1 -y1)-2-(2,4-difluorophenyl)-3-(iV-cycloproyl-N-substituted-amino)-2-propanols were designed and synthesized on the basis of the active site of lanosterol 14α-demethylase. In vitro antifungal activities showed that some of the title compounds had higher antifungal activity and broader antifungal spectrum than fluconazole.     

Design,synthesis and biological evaluation of novel non-azole derivatives as potential antifungal agents

A series of 3-substituted quinazolinones, 2-substituted quinoxalines and 2-substituted benzopyrans were synthesized and evaluated for their antifungal activity in vitro. The new compounds revealed excellent in vitro antifungal activity with broad spectrum. The structure-activity relationships (SARs) of the derivatives were analyzed. Compound 9A2 exhibits better antifungal activity against 5 tested fungi in vitro than fluconazole, especially against Trichophyton rubrum and Microsporum gypseum. This study provides a series of novel lead compounds for the development of non-azole antifungal agents.     

Synthesis and biological evaluation of novel triazole derivatives as antifungal agents

A series of 1-(benzylamino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-l-yl)propan-2-ols compounds were synthesized and evaluated for their antifungal activities in vitro.The results showed that compounds 6A and 6B exhibited good antifungal activity.Compound 6A8 showed the strongest antifungal activity,which was significantly higher than that of the lead compounds and positive-control drugs Fluconazole and Itraconazole.In particular,the antifungal activity of compound 6A8 against Candida albicans and Candida krusei(MIC80 both at 0.00097μg/mL) was 515 and 64 times that of Fluconazole,respectively.The structure-activity relationships of the synthesized compounds were discussed,and the docking model of the target compounds with fungal lanosterol 14α-demethylase (CYP51) was analyzed.     

Synthesis and antifungal activity of trichodermin derivatives

<正>A series of derivatives were synthesized from trichodermin(1) which was an antifungal metabolite produced by Trichoderma taxi sp.nov.Their structures were confirmed by ~1H NMR,MS spectrum.Their antifungal activities were evaluated in vitro.The preliminary structure activity relationships(SAR) results indicated that the double bond,epoxide moiety and ester group were main pharmacophore elements,the stereochemistry of C4 position played a key role as well,and the compounds 1e-1g displayed stronger antifungal activity against Magnaporthe grisea than 1.     

Design,synthesis, and fungicidal activity of novel 1,3,4-oxadiazole derivatives

Employing the intermediate derivatization method (IDM), a series of 1,3,4-oxadiazole derivatives containing arylpyrazoloxyl moiety were designed and synthesized. In vitro bioassays showed that these compounds have moderate to significant fungicidal activity against rice sheath blight and sorghum anthracnose. Furthermore, compound 20 is a promising fungicide for further development.     

Design, synthesis and primary activity of thiomorpholine derivatives as DPP-IV inhibitors

Thirteen thiomorpholine-bearing compounds were designed and synthesized as dipeptidyl peptidase IV（DPP-IV） inhibitors, with natural and non-natural L-amino acids as the starting materials.Their structures were characterized by ¹H NMR,¹³C NMR and HR-MS.The target compounds were screened for the DPP-IV inhibition,and the preliminary SAR result was obtained.Particularly, compounds 4c,4d and 4f with good DPP-IV inhibition in vitro were further evaluated through a mouse oral glucose tolerance test （OGTT）.The preliminary result showed the potential value for further studies on those thiomorpholine-bearing compounds as DPP-IV inhibitors.     

4-氟苯基-2,3-二氢-1,5-苯并[b]硫氮杂类化合物的合成、结构和抑真菌活性

合成了26个4-氟苯基取代的1,5-苯并硫氮杂类化合物2a~2z,其结构经核磁共振波谱、红外光谱和高分辨质谱确证.采用抑菌圈法测试了其对白色念珠菌和新生隐球菌的抑菌活性,结果表明,4-(2,3-二氟苯基)/(2,5-二氟苯基)/(3,4-二氟苯基)-2,3-二氢-1,5-苯并[b]硫氮杂(2a~2f)对新生隐球菌有较强的抑制作用,但杂2a~2z对白色念珠菌均无活性.进一步考察了高活性杂2a~2f对新生隐球菌的最小抑菌浓度(MIC,MIC80)和最小杀菌浓度(MFC),发现其MIC和MFC远低于对照药氟康唑.在此基础上,对杂2a~2f进行了初步构效关系研究,并合成了4个系列21个杂衍生物3a~3f,4a~4f,5a~5f和6a~6c.通过考察其对新生隐球菌的抑菌效果,证明了杂2a~2f分子中的硫原子、碳氮双键结构单元以及2位的甲氧/乙氧羰基是该类化合物抑真菌的必需基团.     

2-甲氧/乙氧羰基-4-氟苯基-1,5-苯并硫氮杂的合成、抑真菌活性及构效关系

以高活性的2-甲氧/乙氧羰基-4-(4-氟苯基)-1,5-苯并硫氮杂A和B为模型化合物,设计合成了11个含氟杂衍生物3a~3k,考察了它们对白色念珠菌和新生隐球菌的抑菌活性.研究结果表明,2-甲氧/乙氧羰基-4-(2-氟苯基)/(3-氟苯基)/(2,4-二氟苯基)-1,5-苯并硫氮杂3a,3b,3d~3f对新生隐球菌有很强的抑菌活性,3c的活性中等,而7位氯代杂3g~3k基本无活性;上述杂对白色念珠菌均无活性.在此基础上,进一步测试了高活性杂3a,3b,3d~3f对新生隐球菌的抑菌浓度梯度、最小抑菌浓度(MIC)和最小杀菌浓度(MFC),发现其MIC和MFC均远低于对照药氟康唑.为了考察杂3a~3f的药效基团,又设计合成了4类杂衍生物4a~4f,5a~5f,6a~6f和7a~7c,通过对其抑菌活性的评价,发现分子中2-甲氧/乙氧羰基和亚胺官能团对杂3a~3f的抑真菌(新生隐球菌)活性起关键作用,硫原子被氧原子或氮原子代替后原杂的活性降低.     

Design and synthesis of novel antifungal triazole derivatives with good activity and water solubility

In order to find novel antifungal agents with good activity and aqueous solubility,a series of SYN-2869 analogues containing a pyridine ring were synthesized and evaluated for their in vitro antifungal activity and water solubility.The results indicated that some compounds showed potent activity against six pathogenic fungi.In particular,the analogue 17a having an isobutyl substitution on the triazolone exhibited significant broad spectrum antifungal activity.In addition,the water solubility of compound 17a was sufficiently improved over SYN-2869.     

Design, synthesis and molecular docking studies of novel triazole antifungal compounds

Based on the active site of Candida albicans lanosterol 14α-demethylase (CACYP51), novel triazole compounds structurally different from the current triazole drugs were designed and synthesized. In vitro antifungal activities showed that compounds 10,11, 16 and 20 exhibited strong activities. In addition, compounds 10,11 and 16 also displayed certain activities against fluconazole-resistant fungi.     

Design and synthesis of novel triazole derivatives containing γ-lactam as potential antifungal agents

A series of novel triazole derivatives containing γ-lactam were designed and synthesized, and their structures were confirmed by ~1H NMR,~(13)CNMR and HRMS. The in vitro antifungal activities of the target compounds were evaluated. The results showed that all of the compounds exhibited stronger activity against the six clinically important fungi tested than fluconazole. 3D and 3E showed comparative activity against the fungi tested except for Candida glabrata and Aspergillus fumigatus as voriconazole. In addition,the docking model for 2A and CYP51 was investigated.     

Development in synthesis and electrochemical properties of thienyl derivatives of carbazole

A convenient and higher yielding synthetic route to N-alkyl-bis(thiophene)- and N-alkyl-bis(ethylenedioxythiophene) carbazole derivatives is reported and their aggregation, and electrochemical properties are characterized. The key step in the synthesis of this group of compounds has been the Stille-type coupling reaction between the N-alkyldibromocarbazole and tin derivatives of thiophene or ethylenedioxythiophene, as the best way for preparation of conjugated N-alkylcarbazole derivatives. For this group of compounds we also present an electrochemical polymerization effect.     

Design,synthesis and biological evaluation of novel arylpiperazine derivatives on human prostate cancer cell lines

A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines(PC-3, LNCa P, and DU145) were evaluated by a CCK-8 assay. Compounds 8, 10, 13, 17 and 20 exhibited strong cytotoxic activities against the tested cancer cell lines(IC_(50)3 μmol/L). In addition, these compounds exhibited weak cytotoxic effects on human epithelial prostate normal cells WPMY-1. The structure–activity relationship(SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data.     

Chiral derivatives of Butenafine and Terbinafine: synthesis and antifungal activity

Two series of allylamines/benzylamines have been synthesised and evaluated for their antifungal activity towards Cryptococcus neoformans. All compounds are chiral derivatives of Butenafine and Terbinafine, having additional substituents at the carbon connected to the central nitrogen atom. In both series, the antifungal activity was strongly dependent on both the steric bulk and the electronic nature of the substituents. Compared to the parent compounds (Butenafine and Terbinafine), the activity was maintained when the hydrogen was replaced with a methyl group. Lower activity was observed for ethyl, whereas introduction of -CH₂F, -CHF₂, -CF₃ or -CN substituents removed all antifungal activity. Testing of (R)- and (S)-N-(4-tert-butylbenzyl)-N-methyl-1-(naphthalen-1-yl)ethanamine against C. neoformans, Cryptococcus diffluens and Trichosporon cutaneum revealed that most of the activity resides in the (R)-enantiomer. The (R)-enantiomer performed as well as, or better (lower MIC values) than Butenafine against each test strain, suggesting that antimycotics based on this compound might be an improvement of existing Butenafine-based formulations.     

Design and synthesis of novel triazole antifungal derivatives based on the active site of fungal lanosterol 14a-demethylase （CYP51）

A series of 1-(1H-1,2,4-triazole-1-y1)-2-(2,4-difluorophenyl)-3-(N-isoproyl-N-substituted-amino)-2-propanols have been designed and synthesized on the basis of the active site of lanosterol 14a-demethylase(CYP51).Their structures were confirmed by MS and ~1H NMR.In vitro antifungal activities of these synthesized compounds were evaluated against eight human pathogenic fungi.The results showed that all title compounds exhibited activity against fungi tested to some extent.Compounds 3c,3d,7a,7b and 7c exhi...     

Electronic structures of carbazole and its derivatives: A semi-empirical study on the substitution effects of carbazole

The electronic structures of carbazole, N-phenylcarbazole (NPC), cyanophenylcarbazole (CPC) and N-ethylcarbazole (NEC) have been calculated using the quantum chemical semi-empirical MINDO/3 method. In this paper, electronic ground states and first singlet excited states of the systems mentioned were investigated. It is observed that the excitation energy of carbazole based on the calculated difference in heats of formation agrees quite well with experimental data obtained from supersonic expansion studies. Calculated energy levels of molecular orbitals and their graphical forms are used qualitatively in elucidating the S₀ → S₁ excitation electronic origin red shifts observed in carbazole derivatives with respect to the electronic origin of the parent carbazole. It is noted that the red shifts are not just a result of the destabilization of the HOMO of carbazole but are also determined by the nature of the substituting moieties. It is also observed that the LUMO of CPC is not derived from the parent carbazole which partially explains the difference in electronic behaviour as compared with the other derivatives.     

New triazole derivatives containing substituted 1, 2, 3-triazole side chains: Design,synthesis and antifungal activity

In order to discover new generation of triazole antifungal agents,a series of novel antifungal triazoles were designed and synthesized by structural simplification of our previously identified triazole-piperdine-heterocycle lead compounds.Several target compounds showed good antifungal activity with a broad spectrum.In particular,compound 7l was highly active against Candida albicans and Candida glabrata.Moreover,compound 7l showed potent in vivo antifungal efficacy in the Caenorhabditis elegans-C.albicans infection model.     

Design, synthesis of novel antifungal triazole derivatives with high activities against Aspergillus fumigatus

Based on the active site of Aspergillus fumigatus lanosterol 14a-demethylase(AF-CYP51),novel triazole compounds weredesigned.Their chemical synthesis and the antifungal activities were reported.The results showed that all the target compoundsexhibited excellent activities with broad spectrum;in which compounds 4,12 and 15 showed comparable activities against A.fumigatus to the control drug itraconazole.     

Design,synthesis, and in vitro antifungal evaluation of novel triazole derivatives bearing alkynyl side chains

In order to explore novel antifungal agents, twenty-seven triazole derivatives featuring an alkyne linker in the side chain were designed and synthesized by the Sonogashira reaction. Most of the target compounds exhibited good antifungal activity against eight human pathogenic fungi, especially excellent activity against Candida and Cryptococcus species, comparing with the reference drugs fluconazole, voriconazole and ravuconazole. Compounds A2 and A3 exhibited in vitro activity against all the tested fungi with MIC₈₀ values ranging from 0.0156 μg/mL to 0.5 μg/mL, which are superior to ravuconazole and fluconazole. SAR and molecular docking study give a clear conclusion that para-fluoro, para-chloro, and para-cyano substituted phenylalkynyl or pyridinylalkynyl side chains may promote triazole antifungal activity.     

One-pot synthesis, antibacterial and antifungal activities of novel 2,5-disubstituted-1,3,4-oxadiazoles

A series of novel 2,5-disubstituted-1,3,4-oxadiazoles have been synthesized from long-chain alkanoic and alkenoic acids. The structures of these compounds have been elucidated by elemental and spectral （IR, ^1H NMR, ^13C NMR, MS） analysis. Furthermore, compounds were screened for in vitro antibacterial activity against the representative panel of two Gram-positive and two Gram- negative bacteria. All the synthesized compounds were also tested for their inhibitory action against five strains of fungus. The various compounds show potent inhibitory action against test organisms. 2007 Abdul Rauf. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.