Design, synthesis and antifungal activity of novel triazoles containing propyl side chains / 药学实践杂志

Objective To study the antifungal activity of a new series of triazole compounds with n-propyl side chain and disubstituted benzyl structure. Methods Eleven target compounds were designed and synthesized. The structures were confirmed by 1H NMR, and some compounds were confirmed by 13C NMR or HRMS. Three fungal strains were selected as experimental strains, and the antifungal activity was tested in vitro according to the standardized antifungal sensitivity test method recommended by National Committee for Clinical Laboratory Standards (NCCLS). Results Compound B11 showed better activity against candida albicans SC5314 than fluconazole and was comparable to posaconazole; Compounds B10, B11 and B4 showed better activity against cryptococcus neoformanis H99 than fluconazole, while compounds B2, B3, B5, B6 and B7 showed similar activity to fluconazole against cryptococcus neoformanis H99; while all compounds showed poor activity against aspergillus fumigatus. Conclusion Some of the target compounds with n-propyl side chain and disubstituted benzyl group structure had certain antifungal activity and could be identified as potential lead antifungal drugs.

Synthesis, characterization and utilization of a new series of 1,2,3-triazole derivatives to neutralize some toxic activities of Bothrops jararaca snake venom

Abstract Snake envenomation is a public health problem, and while serum therapy prevents death, the local effects of venoms can lead to amputations or morbidities. Thus, alternative treatments deserve attention. In this study, we tested eight derivatives of 1,2,3-triazole against some toxic activities of Bothrops jararaca venom. The derivatives were synthesized, and their structures analyzed by infrared and nuclear magnetic resonance. After that, the ability of compounds to inhibit hemolysis, coagulation, proteolysis, hemorrhaging, edema, and lethal activities of B. jararaca venom was investigated. The derivatives were incubated with B. jararaca venom (incubation protocol), administered before (prevention protocol) or after (treatment protocol) injecting venom into the mice. Then, hemorrhaging assay occurred. As a result, most of the derivatives inhibited the activities, even if they were incubated, injected before or after B. jararaca venom. However, the derivatives TRI 07 and TRI 18 seemed to be the most efficient in impairing hemorrhaging. The derivatives showed a low drug score of toxicity based on an in silico technique. Therefore, the derivatives fulfilled physicochemical and biological requirements to become drugs, and they may be a brand new initiative for designing antivenom molecules to complement antivenom therapy to efficiently block tissue necrosis or any other local effects.

Synthesis, antimicrobial and antioxidant activities of pyridyl substituted thiazolyl triazole derivatives

In this present study, 63 different 5-[4-methyl-2-(pyridin-3/4-yl)thiazole-5-yl]-4-substituted-3-substituted benzylthio-4H-1,2,4-triazole derivatives were synthesized, and evaluated for their in vitro antimicrobial activity against various human pathogenic microorganisms and antioxidant activity. The derivatives were synthesized in a multi-step synthesis procedure including triazole and thiazole ring closure reactions, respectively. The synthesized derivatives (A1-24; B1-39) were screened for their antibacterial, antifungal, and antioxidant activities compared to standard agents. The derivatives possessing 3-pyridyl moiety particularly exhibited relatively high antibacterial activity (MIC= < 3.09-500 µg/mL) against Gram-positive bacteria, and compounds possessing 4-pyridyl moiety showed remarkable antioxidant activity

Refinement review of the interactions between triazole antifungal agents and statins based on the optimization of the pre-prescription audit system / 药学实践杂志

Objective To better carries out the review of the interaction between triazole antifungal drugs and statins, ensure drug safety for patients and improve the efficiency of the manual review of pharmacists. Methods The advantageous combination with less interaction between the two kinds of drug was obtained by summarizing the interaction information of triazole antifungal drugs and statins. At the same time, optimizing the process of full manual reviews for drug interaction, and the advantageous combination of the two kinds of drug will be set up in advance on the doctor side of the review system. Doctors can adjust the drug in time according to the prompts of the information system when there is a significant interaction of the two kinds of drug in the prescription or medical order, which is issued by the doctors. Results After optimization, most doctors choose the drug combination of less interaction between the two kinds of drug according to the system prompts. The number of drug combinations of significant interaction which is manually reviewed by pharmacists is significantly reduced (P<0.05), and the review efficiency is improved, the drug safety risks brought by drug interactions to patients are reduced. Conclusion Refinement review of drug interactions between triazole antifungal agents and statins based on the optimization of the pre-audit system plays a positive role in improving the safety of patients’ medication and the efficiency of pharmacists' manual auditing.

Antibacterial and Cytotoxic Effects of Cyclodextrin-Triazole-Titanium Based Nanocomposite

Abstract In this paper, the antibacterial activity of triazole functionalized cyclodextrin (CD.Click) and cyclodextrin-triazole-titanium based nanocomposite (CD.COM) was evaluated. The results indicated that CD.Click and CD.COM perform a wide range of antibacterial activity against both gram positive (Staphylococcus aureus and Bacillus subtilis) and gram negative (Escherichia coli and Pseudomonas aeruginosa) bacteria. The cytotoxic effect of CD.COM was investigated in vitro on cancerous cell lines (cervical cancer, breast carcinoma and sarcoma osteogenic) and fibroblast cells by MTT assay. The cell viability evaluation confirmed that the growth of cancerous cells is inhibited in a dose and time dependent way without any significant effect on the normal fibroblast cells.

One-pot three-component synthesis of new triazolopyrimidine derivatives bearing indole moiety as antiproliferative agents

A new series of triazolopyrimidine derivatives was produced via three-component reactions of suitable aromatic orheteroaromatic carboxaldehyde, 3-amino-1,2,4-triazole, and 3-indolyl-3-oxopropanenitrile in triethylamine as a catalyst.The new compounds have been interpreted using elemental analysis, infrared, mass spectrometry, and nuclear magneticresonance spectroscopy. Antiproliferative effects of the new compounds have been screened on four human cancer types andone human noncancerous type (retinal pigment ephitilial-1) via the 3-(4,5-Dimethylthiazol-2-yl)-2,5-DiphenyltetrazoliumBromide assay. Compounds 4a and 4h have moderate activity against the human colon cancer; most of the compoundswere active toward human lung cancer; compounds 4i, 4h, and 4g were highly active on hormone-dependent human breastcancer, while compounds 4c, 4b, 4h, and 4e were the most active on the hormone-independent human breast. The resultsof this study offer a source for further investigation of selected triazolopyrimidine derivatives as antiproliferative agents.

Synthesis Of Some 2,3-Dihydro-1,3,4-Oxadiazoles And 4,5-Dihydro-1,2,4-Triazoles As Anticancer Agents

Objective: The main objective of this work was to synthesize and evaluate the novel 2,3-dihydro-1,3,4-oxadiazole and 4,5-dihydro-1,2,4-triazole derivatives for cytotoxic activities. Methods: The 2,3-dihydro-1,3,4-oxadiazole derivatives 4a-h were synthesized by cyclization of N'-(substituted-benzylidene) isonicotinohydrazide 3a-e in refluxing acetic anhydride. The 2,3-dihydro-1,3,4-oxadiazole derivatives 4a-h were converted into the corresponding 4,5-dihydro-1,2,4-triazoles 5a-h using ammonia. All the synthesized compounds were identified, depending on the physical and spectral data. Title compounds were assessed for their cytotoxic activity against human cancer cell line (MCF-7) by using Sulforhodamine B (SRB) colorimetric assay. Results: All the synthesized compounds showed characteristic peaks in FTIR, 1HNMR and Mass spectral analysis. The results of the in vitro cytotoxic activity revealed that the compound 4c exhibited equipotent cytotoxic activity with an IC50 value of 8.04 µM when compared with that of standard drug doxorubicin (IC50= 8.02 µM). The reminder compounds have shown good to moderate cytotoxic activities when compared with that of a reference standard. Conclusion: We synthesized a series of title compounds in quantitative yields. Most derivatives showed moderate to good cytotoxic activity.

Synthesis and Antitumor Activity of C-3 Arylidene Thiazolotriazolone of Ofloxacin Derivatives / 中国药学杂志

OBJECTIVE: To discover an efficient strategy for a conversion of the antibacterial activity into an antitumor activity. METHODS: Pharmacophore and scaffold hopping-based rational drug design principles, the title fluoroquinolone C-3 thiazolotriazole unsaturated ketones (6a-6l) were designed and synthesized with a S-triazole ring and α,β-unsaturated ketone, respectively, as an isostere and fused modified group from ofloxacin (1), and their structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity against the tested tumor cell lines was evaluated by a MTT assay. RESULTS: Twelve new title compounds were synthesized, and exhibited more significant potency than parent 1. The title compounds with fluorophenyl or O-methoxyphenyl displayed comparable activity to comparasion doxorubicin. CONCLUSION: A fused heterocyclic unsaturated ketone skeleton as an isostere of the C-3 carboxylic acid group are shown to be an alternative route for further design of lead antitumor fluoroquinolone.

Molecular Docking Studies And Synthesis Of 3, 4 - Disubstituted Triazoles As Mycobacterium Tuberculosis Enoyl-Acp Reductase And Cyp-51 Inhibitors

Objective: To design, synthesize and in vitro antitubercular, antifungal and antioxidant evaluation of some novel mercapto 1, 2, 4–triazole derivatives. Methods: New derivatives were designed by using various software like ACD Lab chemsketch, molinspiration and autodock. Designed molecules are obeying Lipinski’s rule of five and having highest binding score was selected for the synthesis. The synthesized compounds were subjected to TLC, melting point determination, FTIR, 1H NMR, 13C NMR and mass spectral analysis. The newly synthesized compounds were investigated for in vitro antitubercular evaluation by MABA method, antifungal evaluation by cup plate method and antioxidant evaluation by DPPH scavenging assay. Results: A virtual screening was carried out through docking designed compounds into the InhA and CYP-51 binding site to predict if these compounds have an analogous binding mode of the enoyl ACP reductase (InhA) and CYP-51 inhibitors. Three derivatives (4a1, 4a2 and 4a3) were selected for the synthesis with the help of in silico modeling. The selected derivatives were synthesized by a conventional method. All the synthesized compounds showed a characteristic peak in FT IR, 1H and 13C NMR and mass spectroscopic studies. All the selected derivatives showed antitubercular, antifungal and antioxidant activity. Conclusion: The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields. Newer derivatives possess good antitubercular, antifungal and antioxidant activity.

Antimalarial activity of a novel series of artemisinin-derived 1, 2, 3-triazole dimers

Objective: To obtain suitable artimisinin-based drug candidates with high antimalarial activity. Methods: Three different reaction schemes were used to synthesize a total of 15 artemisinin-based compounds. The first synthetic scheme involved the synthesis of diazido aliphatic and aromatic compounds from commercially available dihalides and azido derivatives of artemisinin. The second scheme consisted of the reaction of dibromoaliphatic compounds with sodium azide in dimethylformamide which yielded the desired compounds. Artemisinin-based compounds on treatment with sodium azide and bromotrimethylsilane in dichloromethane produced the most potent compound GB-2. Another potent compound GB-1 was synthesized from artemisinin by treatment with alcohols in the presence of Aberlyst-15 in anhydrous dichloromethane. The third scheme involved the Huisgen 1,3-dipolar cycloaddition between the synthesized aliphatic and aromatic diazides and two alkyne derivatives of artemisinin to obtain the desired artemisinin dimers with average yields. Results: The best in vitro antiplasmodial activity was shown by the compound GB-2 registering IC50 value 0.066 μg/mL against chloroquine-sensitive and 0.865 μg/mL against chloroquine-resistant strains of Plasmodium falciparum. It suppressed 59.0% parasitaemia in vivo of rodent malaria parasite Plasmodium berghei in Swiss albino model at 50 μg/kg body weight dosage. Molecular docking interactions of Plasmodium falciparum ATP6 (PfATP6) protein revealed strong bonding of GB-2 with Thr255 residue which is likely to be the reason for excellent antimalarial activity of this compound. Conclusion: Two compounds GB-1 and GB-2 exhibited excellent in vitro antiplasmodial activity and fair in vivo antimalarial activity. Of the two, GB-2 showed better activity which could be attributed to its strong bonding interactions with Thr255 as evidenced from the molecular docking study. Study helped in identifying artemisinin analogues possessing good antimalarial properties and further research in structural alterations of the selected molecules should be carried out which may result in obtaining potent drug candidates against the malarial parasite.

A new alkaloid from endophytic fungus Aspergillus fumigatus of Euphorbia royleana / 中草药

Objective: To study the secondary metabolites of endophytic fungus Aspergillus fumigatus from Euphorbia royleana. Methods: The fermentation liquor of the fungal strain A. fumigatus was isolated and purified using various chromatographic methods. The structures of the compounds were identified by spectroscopic analysis. Results: Three compounds were isolated and their structures were identified as (R)-2-propylhexyl-2H-1,2,3-triazole-4-carboxylate (1), decumbenone A (2), and (+)-cyclopenol (3). Conclusion: Compound 1 is a new compound isolated from this fungus, which is identified as aspergillus triazolate A.

Antimalarial activity of a novel series of artemisinin-derived 1, 2, 3-triazole dimers

Objective: To obtain suitable artimisinin-based drug candidates with high antimalarial activity. Methods: Three different reaction schemes were used to synthesize a total of 15 artemisinin-based compounds. The first synthetic scheme involved the synthesis of diazido aliphatic and aromatic compounds from commercially available dihalides and azido derivatives of artemisinin. The second scheme consisted of the reaction of dibromoaliphatic compounds with sodium azide in dimethylformamide which yielded the desired compounds. Artemisinin-based compounds on treatment with sodium azide and bromotrimethylsilane in dichloromethane produced the most potent compound GB-2. Another potent compound GB-1 was synthesized from artemisinin by treatment with alcohols in the presence of Aberlyst-15 in anhydrous dichloromethane. The third scheme involved the Huisgen 1,3-dipolar cycloaddition between the synthesized aliphatic and aromatic diazides and two alkyne derivatives of artemisinin to obtain the desired artemisinin dimers with average yields. Results: The best in vitro antiplasmodial activity was shown by the compound GB-2 registering IC

Synthesis and antitumor activity of 3-(5-benzylidenethuzolo-triazlone)fluoroquinolones / 中国药科大学学报

@#To discover an efficient approach for the conversion of antibacterial fluoroquinolones into an antitumor activity, a fused heterocycle ring core, thiazolo［3, 2-b］［1, 2, 4］triazol-5-one was used as an isostere and further modified with an arylidene group. Then, 12 novel C-3 fused heterocyclic unsaturated ketones, 1- ethyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-［6-arylidene-thiazolo［3, 2-b］［1, 2, 4］triazol-5(6H)-one-3-yl］- quinolon-4(1H)-ones(6a-6l), were designed and synthesized from pefloxacin(1). The structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against SMMC-7721, Capan-1 and HL60 cell lines was evaluated. The preliminary pharmacological results demonstrated that the title compounds exhibited more significantly antiproliferative activity than the parent 1. The compounds with fluorophenyl or o-methoxyphenyl showed comparable activity to the comparasion doxorubicin. Thus, it appears to be an alternative route for a fused heterocyclic unsaturated ketone as an isostere of the C-3 carboxylic group to improve the antitumor activity.

Synthesis and cytotoxicity study of cembrane triazole derivatives / 中国药科大学学报

A series of triazole derivatives were designed and synthesized based on a natural product cembrane separated from Croton laevigatus Vahl which showed potential antitumor activity against HeLa cells.Twelve novel compounds were synthesized and their structures were characterized by 1H NMR, 13C NMR and HRMS.Their cytotoxicities in vitro were evaluated for HeLa,K562 and K562/A02 cells by MTT assay.The results showed that some cembrane derivatives possessed antitumor activities.Substituted triazole connected to cembrane derivatives exhibited potent activity toward drug-resistant K562/A02 cells.

Síntese de heteroaril oxazolinas e derivados triazólicos com potencial atividade biológica / Synthesis of heteroaryl oxazolines and triazolic derivatives with potential biological activity

Fungos no ambiente podem ser patogênicos ou oportunistas, dependendo da imunidade do hospedeiro. Existem várias espécies de fungos, por exemplo, Cândida albicans, Cryptococcus e Aspergillus. A primeira espécie fúngica pode ser tratada com o antifúngico fluconazol, que é um composto que contém anéis heterocíclicos 1,2,4-triazólicos. Além disso, existem cepas de fungos que são resistentes à terapia com fluconazol, que é o caso das Cândida krusei, Cândida tropicalis; entre outras. A busca por novos tratamentos envolve o desenvolvimento de novas moléculas sintéticas. Neste trabalho, sintetizamos uma biblioteca de compostos oxazolínicos e seus derivados 1,2,3-triazólicos. A atividade microbiológica foi avaliada contra 10 tipos de Cândida, 2 tipos de Cryptococcus e 2 tipos de Aspergillus. Além disso, foram feitos os testes de hemólise, citotoxicidade, combinações de drogas e permeabilidade de membrana. Os resultados sugerem um alto potencial terapêutico dos compostos e os propomos como potenciais novos antifúngicos

ungi in the environment may be pathogenic or opportunistic depending on the immune status of the host. There are several species of fungi, for example, Candida albicans, Cryptococcus and Aspergillus. The first fungal species can be treated with the antifungal fluconazole, which is a compound containing 1,2,4-triazole heterocyclic rings. In addition, there are strains of fungi that are resistant to fluconazole therapy, which is the case of Candida krusei, Candida tropicalis; among others. The search for new treatments involves the development of new synthetic molecules. In this work, we synthesized a library of oxazoline compounds and their 1,2,3-triazole derivatives. Microbiological activity was evaluated against 10 types of Candida, 2 types of Cryptococcus and 2 types of Aspergillus. In addition, hemolysis, cytotoxicity, drug combinations and membrane permeability were performed. The results suggest the high therapeutic potential of the compounds and we propose them as potential new antifungals

1, 3, 4-Thiadiazole and 1, 2, 4-triazole-3(4 H )-thione bearing salicylate moiety: synthesis and evaluation as anti- Candida albicans

Abstract Dramatically increased occurrence of both superficial and invasive fungal infections has been observed. Candida albicans appear to be the main etiological agent of invasive fungal infections. The anti-C. albicans activity of thiosemicarbazide, 1,3,4-Thiadiazole, and 1,2,4-triazole-3(4H)-thione compounds (compounds 3-23) were investigated. The MIC values of thiadiazole and triazole derivatives 10-23 were in the range of 0.08-0.17 µmol mL-1, while that of fluconazole was 0.052 µmol mL-1. Compound 11 (5-(2-(4-chlorobenzyloxy)phenyl)-N-allyl-1,3,4-thiadiazol-2-amine) and compound 18 (5-(2-(4-chlorobenzyloxy)phenyl)-4-allyl-2H-1,2,4-triazole-3(4H)-thione) were found to be the most active compounds, with MIC values of 0.08 µmol mL-1. The newly synthesized thiadiazole and triazole compounds (compounds 10-23) showed promising anti-Candida activity. The allyl substituent-bearing compounds 11 and 18 exhibited significant anti-Candida albicans activity and showed a binding mode as well as the fluconazole x-ray structure.

Design, synthesis and structure-activity relationship studies of human dihydroorotate dehydrogenase inhibitors / 药学学报

In this study, 1-(3-(4-chlorophenyl)-5-methylthio-1H-1,2,4-triazol-1-yl)-butan-1-one discovered previously in our lab was selected as a inhibitor of human dihydroorotate dehydrogenase (HsDHODH) for structural optimization. The co-crystal of HsDHODH with the hit was obtained and analyzed for guiding the subsequent structural optimization. As a result, a series of novel triazole derivatives were designed and synthesized as potent HsDHODH inhibitors. Among them, compound (3-(4-chlorophenyl)-5-ethylthio-1H-1,2,4-triazol-1-yl)-furan-2-yl-methanone displayed high potency in the inhibition of HsDHODH with an IC50 value of 1.50 μmol·L-1. Meanwhile, the structure-activity relationships were analyzed based on the biological data and the co-crystal structure. These results provide a valuable reference for optimization of 1H-1,2,4-triazole derivatives as HsDHODH inhibitors in the future.

Synthesis and antitumor activity of fluoroquinolone C-3 s-triazole Schiff-base carboxylic acid derivatives from pefloxacin (X) / 中国药科大学学报

To explore a new strategy for further optimization to the C-3 bioisteric heterocyclic ring of fluoroquinolones,twelve novel fluoroquinolone C-3 s-triazole Schiff-base carboxylic acid derivatives(7a-71) were designed and synthesized with both functionalized sulfanylacetic acid and Schiff-base moieties as the modified side-chain for the C-3 bioisosteric s-triazole ring of pefloxacin(1).The structures were characterized by elemental analysis and spectral data,and the in vitro anti-tumor activity of the title compounds against SMMC-7721,L1210 and HL60 cell lines was evaluated.The preliminary pharmacological results demonstrated that the title compounds possessed more significantly anti-proliferative activity than either the parent 1 or the corresponding amine intermediates(6).In particular,the title compound bearing a fluorine atom (7j) and compound bearing a nitro group attached to benzene ring (71) were comparable to the control doxorubicin against SMMC-7721 cells with an IC50 value of micro-molar concentration,respectively.It suggests that s-triazole ring modified with functional side-chain moieties instead of the C-3 carboxylic group is favorable to the improvement of antitumor activity.

Synthesis and antifungal activities of novel triazole derivatives containing sulfur atoms / 药学实践杂志

Objective To design and synthesis novel triazole antifungal derivatives with dithiocarbamates side chain and study the antifungal activities .Methods Nine title compounds were synthesized and characterized by 1 H NMR ,MS spectra . The in vitro antifungal activities of all the compounds were evaluated against eight human pathogenic fungi .Results The title compounds exhibited strong antifungal activities .Some compounds showed excellent activities against Candida albicans with the MIC80 values less than 0 .125 g/ml ,6d was 64 times higher than that of Itraconazole .Conclusion The introduction of the propyl ,sulphur and benzyl moiety to the side chain could affect the antifungal activities .

Orthogonal design optimization in synthesis of novel triazole antifungal com-pounds as key intermediates / 药学实践杂志

Objective To optimize novel triazole antifungal compounds synthesis of key intermediates.Methods The or-thogonal experimental design is used,emphasizing on four factors including the reaction temperature,the weight ratio of mate-rial,reaction time and solvent on the yield.Results The effect of reaction temperature on the reaction yield is the most signifi-cant,followed by reaction time ;the weight ratio of material and solvent on the yield impact is not obvious.Conclusion The new technology has several advantages and yields up to about 50%,less reactive impurities,easy post processing.