- Design and synthesis of novel diosgenin-triazole hybrids targeting inflammation as potential neuroprotective agents
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Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase as the global population ages. Recent studies provide increasing evidence that inflammation plays a key role in the pathogenesis and progression of AD. Diosgenin, an active ingredient in Dioscorea nipponica Makino, is a promising bioactive lead compound in the treatment of Alzheimer's disease, which exhibited anti-inflammatory activity. To search for more efficient anti-Alzheimer agents, a series of novel diosgenin-triazolyl hybrids were designed, synthesized, and their neuroprotective effects against oxygen-glucose deprivation-induced neurotoxicity and LPS-induced NO production were evaluated. Most of these new hybrids displayed better activities than DIO. In particular, the promising compound L6 not only demonstrated an excellent neuroprotective effect but also showed the best anti-inflammatory activity. The structure-activity relationship study illustrated that the introduction of benzyl or phenyl triazole did improve the activity, and the introduction of benzyl triazole was better than that of phenyl triazole. The results we obtained showed that the diosgenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates, and compound L6 has the potential to be an important lead compound for further research.
- Huang, Yi,Huang, Weiwei,Yang, Guixiang,Wang, Rui,Ma, Lei
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supporting information
(2021/05/21)
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- Synthesis, Docking, and Biological activities of novel Metacetamol embedded [1,2,3]-triazole derivatives
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ERα controls the breast tissue development and progression of breast cancer. In our search for novel compounds to target Estrogen Receptor Alpha Ligand-Binding Domain, we identified “N-(3-((1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide” derivatives as lead compounds. The Docking studies indicated good docking score for Metacetamol derivatives when docked into the 1XP6. A series of metacetamol derivatives have been synthesized, characterized and evaluated for cytotoxicity, anti bacterial and anti oxidant activities. Among the tested twelve hybrid compounds, “7a, 7g, 7h and 7i” derivatives showed promising cytotoxicity with IC50 value of 50 value of 30 μM, whereas Compounds “7a, 7b, 7c, 7d, 7g, 7j, 7k and 7l” showed moderate anti bacterial activity with the MIC value of 300 μM.
- Battu, Satyanarayana,Joolakanti, Hima Bindhu,Kamepalli, Ramanjaneyulu,Miryala, Jeevanreddy
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- Synthesis and muscarinic acetylcholine receptor (mAChR) antagonist activity of substituted piperazine-triazoles
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This study describes synthesis of a series of piperazine-triazole derivatives and their ex vivo evaluation for preliminary muscarinic acetylcholine receptor (mAChR) blocking activity on rat ileum model. A molecule based on benzonitrile piperazine triazole scaffold showed good tissue relaxation and blocking of neurotransmitter ACh in the ex vivo experiment. Graphic abstract: [Figure not available: see fulltext.]
- Acharya, Badri Narayan,Ghorpade, RamaRao,Singh, Kshetra Pal,Kumar, Deo,Nayak, Sabita
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p. 357 - 366
(2021/03/16)
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- Dipolar HCP materials as alternatives to DMF solvent for azide-based synthesis
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Hypercrosslinked polymers HCP-DMF and HCP-DMF-SO3H containing abundant and flexible DMF moieties were designed and synthesized. Benefitting from the solvation microenvironment provided by the pseudo-DMF moities, the polar HCPs manifested outstanding performances in the conversions of NaN3 to benzylic azides and 1,2,3-triazoles in EtOH (95%), respectively, avoiding the use of risky DMF and improving the separation processes of the products.
- Bai, Rongxian,Gao, Feng,Gu, Yanlong,Li, Minghao
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p. 7499 - 7505
(2021/10/12)
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- Design, synthesis, and evaluation of metronidazole-1,2,3-triazole derivatives as potent urease inhibitors
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A new series of metronidazole-1,2,3-triazole derivatives 6a–o was synthesized and evaluated as Helicobacter pylori urease inhibitors. All the synthesized compounds were more potent than standard inhibitor thiourea against urease. Among the synthesized compounds, compound 6f (IC50 = 1.975 ± 0.25?μM) with inhibitory activity around 11-fols more than thiourea (IC50 = 22.00 ± 0.14?μM) was the most potent compound. Kinetic study of this compound revealed that compound 6f inhibited urease in an uncompetitive mode. Based on molecular modeling study, compound 6f pointed toward the bi-nickel center and stabilized by H-bond and T-shape π–π hydrophobic interactions with the critical residues His492 and Asp633. Moreover, it anchored to the helix-turn-helix motif in the active site cavity through interaction with His593 and Arg609. Consequently, it proposed that compound 6f through stabilization of active site flap inhibited urease activity.
- Rezaei, Elham Babazadeh,Abedinifar, Fahimeh,Azizian, Homa,Montazer, Mohammad Nazari,Asadi, Mehdi,Hosseini, Samanesadat,Sepehri, Saghi,Mohammadi-Khanaposhtani, Maryam,Biglar, Mahmood,Larijani, Bagher,Amanlou, Massoud,Mahdavi, Mohammad
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p. 4217 - 4226
(2021/04/26)
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- Synthesis of 1,2,3,triazole modified analogues of hydrochlorothiazide via click chemistry approach and in-vitro α-glucosidase enzyme inhibition studies
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The current study was aimed to discover potent inhibitors of α-glucosidase enzyme. A 25 membered library of new 1,2,3-triazole derivatives of hydrochlorothiazide (1) (HCTZ, a diuretic drug also being used for the treatment of high blood pressure) was synt
- Baheej, M. A. A.,Choudhary, M. Iqbal,Haniffa, Haroon M.,Iqbal, Shazia,Rizvi, Fazila,Siddiqui, Hina,Ullah, Saeed,Wahab, Atia-tul
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- Cyclic Diaryl λ3-Bromanes: A Rapid Access to Molecular Complexity via Cycloaddition Reactions
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Biaryls have widespread applications in organic synthesis. However, sequentially polysubstituted biaryls are underdeveloped due to their challenging preparation. Herein, we report the synthesis of dissymetric 2,3,2′,3′,4-substituted biaryls via pericyclic reactions of cyclic diaryl λ3-bromanes. The functional groups tolerance and atom economy allow access to molecular complexity in a single reaction step. Continuous flow protocol has been designed for the scale-up of the reaction, while postfunctionalizations have been developed taking advantage of the residual Br-atom.
- Lanzi, Matteo,Ali Abdine, Racha Abed,De Abreu, Maxime,Wencel-Delord, Joanna
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supporting information
p. 9047 - 9052
(2021/12/06)
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- New 1,2,3-triazole–(thio)barbituric acid hybrids as urease inhibitors: Design, synthesis, in vitro urease inhibition, docking study, and molecular dynamic simulation
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A new series of 1,2,3-triazole–(thio)barbituric acid hybrids 8a–n was designed and synthesized on the basis of potent pharmacophores with urease inhibitory activity. Therefore, these compounds were evaluated against Helicobacter pylori urease. The obtained result demonstrated that all the synthesized compounds, 8a–n, were more potent than the standard urease inhibitor, hydroxyurea. Moreover, among them, compounds 8a, 8c–e, 8g,h, and 8k,l exhibited higher urease inhibitory activities than the other standard inhibitor used: thiourea. Docking studies were performed with the synthesized compounds. Furthermore, molecular dynamic simulation of the most potent compounds, 8e and 8l, showed that these compounds interacted with the conserved residues Cys592 and His593, which belong to the active site flap and are essential for enzymatic activity. These interactions have two consequences: (a) blocking the movement of a flap at the entrance of the active site channel and (b) stabilizing the closed active site flap conformation, which significantly reduces the catalytic activity of urease. Calculation of the physicochemical and topological properties of the synthesized compounds 8a–n predicted that all these compounds can be orally active. The ADME prediction of compounds 8a–n was also performed.
- Asgari, Mohammad S.,Azizian, Homa,Nazari Montazer, Mohammad,Mohammadi-Khanaposhtani, Maryam,Asadi, Mehdi,Sepehri, Saghi,Ranjbar, Parviz R.,Rahimi, Rahmatollah,Biglar, Mahmood,Larijani, Bagher,Amanlou, Massoud,Mahdavi, Mohammad
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- A Nanosized Propeller-like Polyoxometalate-linked Copper(I)-Resorcin[4]arene for Efficient Catalysis
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The design and assembly of polyoxometalate-resorcin[4]arene-based metal-organic molecular materials are particularly attractive for their elegant structures and potential functions. By applying a newly designed resorcin[4]arene ligand (TPC4R-II), a copper(I)-coordinated polyoxometalate-based metal-organic molecular material, namely, [CuI6(Br)3(TPC4R-II)3(PMo12O40)]·8H2O (1), was rationally assembled. Three copper(I)-coordinated resorcin[4]arenes are held together by a central [PMo12O40]3- to yield a supramolecular propeller. 1 features efficient catalytic performances for oxidation desulfurization (ODS) and azide-alkyne cycloaddition (AAC) reactions. This work affords a feasible method for the nanosized polyoxometalate-based metal-resorcin[4]arene assemblies by well combinating two types of large composites as well as low coordination metal cations.
- Guo, Ting-Ting,Ma, Jian-Fang,Xiong, Yan-Ling,Yang, Jin,Yu, Ming-Yue
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p. 15402 - 15409
(2020/11/02)
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- Synthesis and in vitro cytotoxicity and antibacterial activity of novel1,2,3-triazol-5-yl-phosphonates
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Novel1,2,3-triazol-5-yl-phosphonates were prepared by the copper(I)-catalyzed domino reaction of phenylacetylene, organic azides and dialkyl phosphites. The process was optimized on the synthesis of the dibutyl (1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)phosphonate in respect of the catalyst, the base and the solvent, as well as of the reaction parameters (molar ratio of the starting materials, atmosphere, temperature and reaction time). The method elaborated could be applied to a range of organic azides and dialkyl phosphites, which confirmed the large scope and the functional group tolerance. The in vitro cytotoxicity on different cell lines and the antibacterial activity of the synthesized1,2,3-triazol-5-yl-phosphonates was explored. According to the IC50 values determined, only modest antibacterial effect was detected, while some derivatives showed moderate activity against human promyelocytic leukemia HL-60 cells.
- Bálint, Erika,Hackler, László,Kari, Beáta,Puskás, László G.,Szabó, Pál Tamás,Tóth, Emese,Tripolszky, Anna
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- Design, synthesis and antibacterial activity evaluation of novel 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives
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In this paper, a novel series of 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives are synthesized in two steps. The first step involved Ugi multicomponent reaction of β-alanine, o-(propargyl)benzaldehyde and i
- Zarei, Samaneh,Komeili, Golzar,Bahadorikhalili, Saeed,Yahya-Meymandi, Azadeh,Karami-Zarandi, Morteza,Larijani, Bagher,Biglar, Mahmood,Sadat Ebrahimi, Seyed Esmaeil,Mahdavi, Mohammad
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p. 4254 - 4261
(2020/09/21)
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- Design, synthesis, biological evaluation, and docking study of new acridine-9-carboxamide linked to 1,2,3-triazole derivatives as antidiabetic agents targeting α-glucosidase
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A new series of acridine-9-carboxamide-1,2,3-triazole derivatives 7a-m were designed, synthesized, and evaluated as novel α-glucosidase inhibitors. Acridine-9-carboxamide-1,2,3-triazole scaffold has been designed by combination of effective moieties from potent α-glucosidase inhibitors. Most of the synthesized compounds were more potent than standard inhibitor acarbose. Among the title compounds, the most potent compounds were compounds 7j, 7k, and 7a with IC50 values of 120.2 ± 1.0, 151.1 ± 1.4, and 157.6 ± 1.6 μM, respectively (IC50 value of acarbose = 750.0 ± 10.0 μM). Docking study of the most potent compounds demonstrated that these compounds formed stable complexes with α-glucosidase active site. Anti-α-amylase assay of compounds 7j, 7k, and 7a was performed and no activity was observed. in vitro cytotoxicity assay of the latter compounds revealed that these compounds were not cytotoxic toward human normal (HDF) and cancer (MCF-7) cell lines. ADME and toxicity prediction of compounds 7j, 7k, and 7a were also performed.
- Asgari, Mohammad S.,Tahmasebi, Behnam,Mojtabavi, Somayeh,Faramarzi, Mohammad A.,Rahimi, Rahmatollah,Ranjbar, Parviz R.,Biglar, Mahmood,Larijani, Bagher,Rastegar, Hossein,Mohammadi-Khanaposhtani, Maryam,Mahdavi, Mohammad
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p. 4348 - 4357
(2020/10/12)
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- Synthesis of cinnamic acid derivatives and leishmanicidal activity against Leishmania braziliensis
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Leishmania braziliensis is one of the pathogenic agents of cutaneous and mucocutanoeous leishmaniasis. There are no validated vaccines to prevent the infection and the treatment relies on drugs that often present severe side effects, which justify the efforts to find new potential antileishmanial drugs. An alternative to promote the discovery of new drugs would be the association of different chemical groups of bioactive compounds. Here we describe the synthesis and bioactivity evaluation against L. braziliensis of cinnamic acid derivatives possessing isobenzofuranone and 1,2,3-triazole functionalities. We tested 25 compounds at 10 μM concentration against extracellular promastigotes and intracellular amastigotes during macrophage infection. Most compounds were more active against amastigotes than to promastigotes. The derivatives (E)-3-oxo-1,3-dihydroisobenzofuran-5-yl-(3,4,5-trimethoxy) cinnamate (5c), (1-(3,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl cinnamate (9g), and (1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl cinnamate (9l) were the most effective presenting over 80% toxicity on L. braziliensis amastigotes. While compound 5c is a cinnamate with an isobenzofuranone portion, 9g and 9l are triazolic cinnamic acid derivatives. The action of these compounds was comparable to amphotericin B used as positive control. Ultrastructural analysis revealed that 5c-treated parasites showed impaired cytokinesis and apoptosis triggering. Taken together, these results highlight the potential of cinnamic acid derivatives in development of novel anti-leishmanial drugs.
- Rodrigues, Michelle Peixoto,Tomaz, Deborah Campos,?ngelo de Souza, Luciana,Onofre, Thiago Souza,Aquiles de Menezes, Wemerson,Almeida-Silva, Juliana,Suarez-Fontes, Ana Márcia,Rogéria de Almeida, Márcia,Manoel da Silva, Adalberto,Bressan, Gustavo Costa,Vannier-Santos, Marcos André,Rangel Fietto, Juliana Lopes,Teixeira, Róbson Ricardo
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- Polyoxometalate-Bridged Cu(I)- And Ag(I)-Thiacalix[4]arene Dimers for Heterogeneous Catalytic Oxidative Desulfurization and Azide-Alkyne "click" Reaction
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Two remarkable polyoxometalate-bridged Cu(I)- and Ag(I)-thiacalix[4]arene dimers, namely, [Cu4(SiW12O40)(L)2(DMF)2]·2EtOH·DMF (1-Cu) and [Ag4(PMo12O40)(L)2]·OH (1-Ag), were prepared by using a new thiacalix[4]arene, metal cation and polyoxometalate (L = tetra[2-(ethylthio)-1-methyl-1H-imidazole]-thiacalix[4]arene). In 1-Cu and 1-Ag, two thiacalix[4]arenes were linked together by one [SiW12O40]4- or [PMo12O40]3- anion via two metal cations to give a molecular dimer. Further, adjacent dimers were extended into a high-dimensional supramolecular architecture through hydrogen bonds. Markedly, these molecular dimers are exceedingly stable in organic solvents and then were employed as efficient catalysts for catalytic oxidation desulfurization as well as the azide-alkyne "click" reaction.
- Yu, Ming-Yue,Guo, Ting-Ting,Shi, Xiao-Chuan,Yang, Jin,Xu, Xianxiu,Ma, Jian-Fang,Yu, Zhen-Tao
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supporting information
p. 11010 - 11019
(2019/08/26)
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- Highly regioselective and sustainable solar click reaction: A new post-synthetic modified triazole organic polymer as a recyclable photocatalyst for regioselective azide-alkyne cycloaddition reaction
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The synthesis of pharmaceutically active 1,2,3-triazoles has been continuously scrutinized in the search for unique and effective catalysts to make the process efficient, green, and sustainable. Here, we are presenting a new visible light active Ni(ii) cyclam-integrated triazole-linked organic polymer (Ni-TLOP) photocatalyst for the synthesis of 1,2,3-triazole compounds with excellent efficiency and regioselectivity. The reaction was studied for a series of substrates and the absolute regioselectivity of a representative triazole product has also been confirmed by X-ray crystallography. The proficiency and chemical orthogonality of the Ni-TLOP are remarkable and it shows enhanced efficiency and regioselectivity. The use of a recyclable photocatalyst and non-hazardous reagents makes the catalytic system sustainable and environmentally friendly. This photocatalyzed click reaction technique has been successfully applied to the expedient synthesis of one of the most sold anti-epileptic drugs rufinamide.
- Yadav, Dolly,Singh, Nem,Kim, Tae Wu,Kim, Jae Young,Park, No-Joong,Baeg, Jin-Ook
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supporting information
p. 2677 - 2685
(2019/06/13)
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- Synthesis of (1,2,3‐triazol‐4‐yl)methyl phosphinates and (1,2,3‐Triazol‐4‐yl)methyl phosphates by copper‐catalyzed azide‐alkyne cycloaddition
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An efficient and practical method was developed for the synthesis of new (1,2,3‐triazol‐4‐yl)methyl phosphinates and (1,2,3‐triazol‐4‐yl)methyl phosphates by the copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) of organic azides and prop‐2‐ynyl phos
- Tripolszky, Anna,Németh, Krisztina,Szabó, Pál Tamás,Bálint, Erika
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- Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2
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Sirtuins (SIRTs), class III HDAC (Histone deacetylase) family proteins, are associated with cancer, diabetes, and other age-related disorders. SIRT1 and SIRT2 are established therapeutic drug targets by regulating its function either by activators or inhi
- Manjula, Ramu,Gokhale, Nikhila,Unni, Sruthi,Deshmukh, Prashant,Reddyrajula, Rajkumar,Srinivas Bharath,Dalimba, Udayakumar,Padmanabhan, Balasundaram
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- Synthesis and evaluation of novel triazolyl quinoline derivatives as potential antileishmanial agents
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The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover novel series of 25 compounds for the development of new antileishmanial agents. A series of triazolyl 2-methyl-4-phenylquinoline-3-carboxylate derivatives has been synthesized via click chemistry inspired molecular hybridization approach and evaluated against Leishmania donovani. Most of the screened derivatives exhibited significant in vitro anti-leishmanial activity against promastigote (IC50 ranging from 2.43 to 45.75 μM) and intracellular amastigotes (IC50 ranging from 7.06 to 34.9 μM) than the control, miltefosine (IC50 = 8.4 μM), with less cytotoxicity in comparison to the standard drugs. Overall results revealed that prototype signify a new structural lead for antileishmanial chemotherapy.
- Upadhyay, Akanksha,Kushwaha, Pragati,Gupta, Sampa,Dodda, Ranga Prasad,Ramalingam, Karthik,Kant, Ruchir,Goyal, Neena,Sashidhara, Koneni V.
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p. 172 - 181
(2018/05/25)
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- Novel indole and triazole based hybrid molecules exhibit potent anti-adipogenic and antidyslipidemic activity by activating Wnt3a/β-catenin pathway
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Obesity and dyslipidemia is the two facet of metabolic syndrome, which needs further attention. Recent studies indicate triazole and indole derivatives have remarkable anti-obesity/antidyslipidemic activity. To harness the above-mentioned potential, a series of novel triazole clubbed indole derivatives were prepared using click chemistry and evaluated for anti-adipogenic activity. Based on the structure-activity relationship, essential functional groups which potentiate anti-adipogenic activity were identified. The lead compound 13m exhibited potent anti-adipogenic activity compared to its parent compounds with the IC-50 value of 1.67 μM. Further evaluation of anti-adipogenic activity was conducted in different cell lines such as C3H10T1/2 and hMSC with positive result. The anti-adipogenic effect of compound 13m was most prominent in the early phase of adipogenesis, which is driven by the G1 to S phase cell cycle arrest during mitotic clonal expansion. The mechanistic study suggests that compound 13m exhibit anti-adipogenic property by activating Wnt3a/β-catenin pathway, a known suppressor of key adipogenic genes PPARγ and C/EBPα. It is noteworthy that the compound 13m also reduced serum triglyceride, LDL and total cholesterol in Syrian Golden hamster model of dyslipidemia. The anti-adipogenic activity of compound 13m can also be correlated with decreased expression of PPARγ and increased expression of β-catenin in epididymal white adipose tissue (eWAT) in vivo. The compound 13m also increased the expression of genes involved in reverse cholesterol transport (RCT) such as PPARα and LXR1α indicating another mechanism by which compound 13m ameliorates dyslipidemia in Syrian Golden hamster model. Overall this study provides a unique perspective into the anti-adipogenic/antidyslipidemic property of triazole and indole hybrids molecules with further scope to increase the anti-adipogenic potency for therapeutic intervention of obesity and metabolic syndrome.
- Rajan, Sujith,Puri, Surendra,Kumar, Durgesh,Babu, Madala Hari,Shankar, Kripa,Varshney, Salil,Srivastava, Ankita,Gupta, Abhishek,Reddy, M. Sridhar,Gaikwad, Anil N.
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supporting information
p. 1345 - 1360
(2017/11/20)
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- Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus
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Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a “triazole tail” occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02–1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.015 μM, CC50 = 40.15 μM), pyrrolidin-1-ylmethanone (3b8, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.014 μM, CC50 = 58.09 μM) and morpholinomethanone (3b9, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.027 μM, CC50 = 180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed.
- Tian, Ye,Liu, Zhaoqiang,Liu, Jinghan,Huang, Boshi,Kang, Dongwei,Zhang, Heng,De Clercq, Erik,Daelemans, Dirk,Pannecouque, Christophe,Lee, Kuo-Hsiung,Chen, Chin-Ho,Zhan, Peng,Liu, Xinyong
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p. 339 - 350
(2018/04/10)
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- Hit discovery of Mycobacterium tuberculosis inosine 5′-monophosphate dehydrogenase, GuaB2, inhibitors
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Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5′-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.
- Sahu, Niteshkumar U.,Singh, Vinayak,Ferraris, Davide M.,Rizzi, Menico,Kharkar, Prashant S.
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p. 1714 - 1718
(2018/05/05)
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- Steering Siglec–Sialic Acid Interactions on Living Cells using Bioorthogonal Chemistry
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Sialic acid sugars that terminate cell-surface glycans form the ligands for the sialic acid binding immunoglobulin-like lectin (Siglec) family, which are immunomodulatory receptors expressed by immune cells. Interactions between sialic acid and Siglecs regulate the immune system, and aberrations contribute to pathologies like autoimmunity and cancer. Sialic acid/Siglec interactions between living cells are difficult to study owing to a lack of specific tools. Here, we report a glycoengineering approach to remodel the sialic acids of living cells and their binding to Siglecs. Using bioorthogonal chemistry, a library of cells with more than sixty different sialic acid modifications was generated that showed dramatically increased binding toward the different Siglec family members. Rational design reduced cross-reactivity and led to the discovery of three selective Siglec-5/14 ligands. Furthermore, glycoengineered cells carrying sialic acid ligands for Siglec-3 dampened the activation of Siglec-3+ monocytic cells through the NF-κB and IRF pathways.
- Büll, Christian,Heise, Torben,van Hilten, Niek,Pijnenborg, Johan F. A.,Bloemendal, Victor R. L. J.,Gerrits, Lotte,Kers-Rebel, Esther D.,Ritschel, Tina,den Brok, Martijn H.,Adema, Gosse J.,Boltje, Thomas J.
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supporting information
p. 3309 - 3313
(2017/03/17)
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- Synthesis and antibacterial activity of novel 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs
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Three novel structural series of 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs were designed, synthesized and evaluated for their in vitro antibacterial activity. All the target compounds exhibited excellent activity against erythromycin-susceptible Streptococcus pyogenes, and significantly improved activity against three phenotypes of erythromycin-resistant Streptococcus pneumoniae compared with clarithromycin and azithromycin. Among the three series of azithromycin analogs, the novel series of 11,4″-disubstituted azithromycin analogs 9a–k exhibited the most effective and balanced activity against susceptible and resistant bacteria. Among them, compound 9j showed the most potent activity against Staphylococcus aureus ATCC25923 (0.008?μg/mL) and Streptococcus pyogenes R2 (1?μg/mL). Besides, all the 11,4″-disubstituted azithromycin analogs 9a–k except 9f shared the identical activity with the MIC value 0.002?μg/mL against Streptococcus pyogenes S2. Furthermore, compounds 9g, 9h, 9j and 9k displayed significantly improved activity compared with the references against all the three phenotypes of resistant S. pneumoniae. Particularly, compound 9k was the most effective (0.06, 0.03 and 0.125?μg/mL) against all the erythromycin-resistant S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, exhibiting 2133, 133 and 2048-fold more potent activity than azithromycin, respectively.
- Wang, Yinhu,Cong, Chao,Chern Chai, Wern,Dong, Ruiqian,Jia, Li,Song, Di,Zhou, Ziteng,Ma, Shutao
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supporting information
p. 3872 - 3877
(2017/07/27)
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- Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents
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Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC50 = 7.5 μM) and showed better activity than the lead compound (xanthotoxin, IC50 > 100 μM) and the reference drug (5-fluorouracil, IC50 = 29.6 μM) did. The IC50 value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents.
- Shen, Qing-Kun,Liu, Chuan-Feng,Zhang, Hong-Jian,Tian, Yu-Shun,Quan, Zhe-Shan
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supporting information
p. 4871 - 4875
(2017/09/27)
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- Leishmanicidal and cytotoxic activity of hederagenin-bistriazolyl derivatives
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Aiming to obtain new potent leishmanicidal and cytotoxic compounds from natural sources, the triterpene hederagenin was converted into several new 1,2,3-triazolyl derivatives tethered at C-23 and C-28. For this work hederagenin was isolated from fruits of
- Rodríguez-Hernández, Diego,Barbosa, Luiz C.A.,Demuner, Antonio J.,Nain-Perez, Amalyn,Ferreira, Sebasti?o R.,Fujiwara, Ricardo T.,de Almeida, Raquel M.,Heller, Lucie,Csuk, René
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supporting information
p. 624 - 635
(2017/10/13)
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- One-pot synthesis of oxoisoindoline-1,2,3-triazole hybrid by a Ugi–click reaction
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1,2,3-Triazole-3-oxoisoindoline-1-carboxamide system was successfully synthesized by using a combination of Ugi and click reactions. This two-step, one-pot synthesis was started by the reaction of 2-formyl benzoic acid, propargyl amine, and cyclohexyl iso
- Akrami, Sara,Firoozpour, Loghman,Goli-Garmroodi, Fereshteh,Moghimi, Setareh,Mahdavi, Mohammad,Zonouzi, Afsaneh,Foroumadi, Alireza
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p. 1708 - 1712
(2016/10/21)
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- Synthesis of novel 5-[(1,2,3-triazol-4-yl)methyl]-1-methyl-3H-pyridazino[4,5-b]indol-4-one derivatives by click reaction and exploration of their anticancer activity
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A series of pyridazino[4,5-b]indole derivatives containing alkyl-, benzyl- and phenacyl-substituted 1,2,3-triazolylmethyl units was synthesized using click chemistry approach. All 30 compounds of the series were screened in vitro against four cancer cell lines, viz. breast cancer cells MDA-MB-231 and MCF 7, human primary glioblastoma U-87 and human neuroblastoma IMR-32 cell lines. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. The IC50 value of compounds 7v and 7x against human neuroblastoma IMR-32 cell line is 0.07 and 0.04 μM, respectively. Among the tested compounds, ten compounds showed IC50 value less than 1 μM against MDA-MB-231 cells, whereas against IMR-32 cells, nine compounds and, against U-87 cells, six compounds showed similar inhibition activity. Further, these molecules exhibited prominent binding affinity and docking scores in the molecular simulation study with the target enzyme PI3 kinase. Graphical Abstract: This paper illustrates the synthesis of new fused indole-pyridazinone derivatives containing substituted 1,2,3-triazoles via click chemistry approach. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. [Figure not available: see fulltext.]
- Panathur, Naveen,Gokhale, Nikhila,Dalimba, Udayakumar,Koushik, Pulla Venkat,Yogeeswari, Perumal,Sriram, Dharmarajan
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p. 135 - 148
(2016/01/25)
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- Novel hederagenin-triazolyl derivatives as potential anti-cancer agents
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A series of novel aryl-1H-1,2,3-triazol-4-yl methylester and amide derivatives of the natural product hederagenin was synthesized aiming to develop new antitumor agents, using Huisgen 1,3-dipolar cycloaddition reactions, with yields between 35% and 95%. T
- Rodríguez-Hernández, Diego,Demuner, Antonio J.,Barbosa, Luiz C.A.,Heller, Lucie,Csuk, René
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p. 257 - 267
(2016/04/05)
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- Piperazinyl-containing 1, 2, 3-triazole antifungal compound and its preparation method and application
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The invention relates to a piperazine-containing 1,2,3-triazole antifungal compound and pharmaceutically acceptable salts thereof. A structure general formula of the 1,2,3-triazole antifungal compound is shown in the specification, wherein R can be haloge
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Paragraph 0055; 0062; 0063
(2016/10/08)
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- Discovery of 7-Methyl-10-Hydroxyhomocamptothecins with 1,2,3-Triazole Moiety as Potent Topoisomerase I Inhibitors
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Homocamptothecin is emerging as an important topoisomerase I inhibitor originating in natural product camptothecin. We report the modifications and SAR of homocamptothecin on position C10 to develop potent topoisomerase I inhibitors for anticancer drug di
- Xu, Xiguo,Wu, Yuelin,Liu, Wenfeng,Sheng, Chuanquan,Yao, Jianzhong,Dong, Guoqiang,Fang, Kun,Li, Jin,Yu, Zhiliang,Min, Xiao,Zhang, Huojun,Miao, Zhenyuan,Zhang, Wannian
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p. 398 - 403
(2016/10/19)
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- New Series of BPL Inhibitors To Probe the Ribose-Binding Pocket of Staphylococcus aureus Biotin Protein Ligase
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Replacing the labile adenosinyl-substituted phosphoanhydride of biotinyl-5′-AMP with a N1-benzyl substituted 1,2,3-triazole gave a new truncated series of inhibitors of Staphylococcus aureus biotin protein ligase (SaBPL). The benzyl group presents to the
- Feng, Jiage,Paparella, Ashleigh S.,Tieu, William,Heim, David,Clark, Sarah,Hayes, Andrew,Booker, Grant W.,Polyak, Steven W.,Abell, Andrew D.
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supporting information
p. 1068 - 1072
(2016/12/18)
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- O-(triazolyl)methyl carbamates as a novel and potent class of Fatty Acid Amide Hydrolase (FAAH) inhibitors
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Inhibition of fatty acid amide hydrolase (FAAH) activity is under investigation as a valuable strategy for the treatment of several disorders, including pain and drug addiction. A number of potent FAAH inhibitors belonging to different chemical classes have been disclosed to date; O-aryl carbamates are one of the most representative families. In the search for novel FAAH inhibitors, a series of O-(1,2,3-triazol-4-yl)methyl carbamate derivatives were designed and synthesized exploiting a coppercatalyzed [3+2] cycloaddition reaction between azides and alkynes (click chemistry). Exploration of the structure-activity relationships within this new class of compounds identified potent inhibitors of both rat and human FAAH with IC50 values in the single-digit nanomolar range. In addition, these derivatives showed improved stability in rat plasma and kinetic solubility in buffer with respect to the lead compound. Based on the results of the study, the novel analogues identified can be considered to be promising starting point for the development of new FAAH inhibitors with improved drug-like properties.
- Colombano, Giampiero,Albani, Clara,Ottonello, Giuliana,Ribeiro, Alison,Scarpelli, Rita,Tarozzo, Glauco,Daglian, Jennifer,Jung, Kwang-Mook,Piomelli, Daniele,Bandiera, Tiziano
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supporting information
p. 380 - 395
(2015/02/05)
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- Design and synthesis of N-hydroxytriazole-4-carboxamides as HIV integrase inhibitors
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A series of N-hydroxytriazole-4-carboxamide derivatives were synthesized, and their potential HIV integrase inhibitory activities were evaluated.
- Bai, Yue-Xia,Li, Long-Ji,Wang, Xiao-Li,Zeng, Cheng-Chu,Hu, Li-Ming
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p. 423 - 429
(2015/06/17)
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- PROCESS FOR PREPARATION OF 1,2,3-TRIAZOLE-4 CARBOXAMIDES
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The invention relates to the preparation of 1,2,3-triazole-4-carboxamide of general Formula I: wherein R1 and R2 may be the same or different and are selected from H, F, Cl, Br, I, OR, C(O)R, NH2, NHR or NR2. R can be a linear or branched alkyl group, for example a C1-C4 alkyl group. In exemplary embodiments, R1 and R2 are independently selected from H, F, Cl, Br, and I. The compound of Formula I can be Rufinamide.
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Paragraph 0059; 0062
(2014/06/23)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Paragraph 00309; page 128
(2014/08/19)
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- Alkyne-azide cycloadditions with copper powder in a high-pressure continuous-flow reactor: High-temperature conditions versus the role of additives
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A safe and efficient flow-chemistry-based procedure is presented for 1,3-dipolar cycloaddition reactions between organic azides and acetylenes. This simple and inexpensive technique eliminates the need for costly special apparatus and utilizes Cu powder a
- Oetvoes, Sandor B.,Mandity, Istvan M.,Kiss, Lorand,Fueloep, Ferenc
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p. 800 - 808
(2013/05/09)
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- Synthesis and antifungal activity of the novel triazole derivatives containing 1,2,3-triazole fragment
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A series of fluconazole analogues containing 1,2,3-triazole fragment have been designed and synthesized on the basis of the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by 1H NMR, 13C NMR and LC-MS. The MIC80 values indicate that the target compounds 1a-r showed higher activities against nearly all the fungi tested to some extent except against Aspergillus fumigatus. Compounds 1c, e, f, l and p showed 128 times higher activity (with the MIC 80 value of 0.0039 mg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls.
- Yu, Shichong,Wang, Nan,Chai, Xiaoyun,Wang, Baogang,Cui, Hong,Zhao, Qingjie,Zou, Yan,Sun, Qingyan,Meng, Qingguo,Wu, Qiuye
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p. 1215 - 1222
(2013/11/06)
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- Synthesis and anti-leishmanial activity of 5-(5-nitrofuran-2-yl)-1,3,4- thiadiazol-2-amines containing N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl] moieties
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A novel series of 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-amines were synthesized by introducing N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl] moiety as a new functionality on the C-2 amine of thiadiazole ring via click chemistry. The title compounds namely, N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-5-(5- nitrofuran-2-yl)-1,3,4-thiadiazol-2-amines (3a-n) were characterized by IR, NMR and MS spectra. These compounds were evaluated for their in vitro anti-leishmanial activity against promostigote form of the Leishmania major. Most compounds exhibited good anti-leishmanial activity against the promastigote form of L. major. The most active compound against promostigotes was found to be 4-methylbenzyl analog 3i, which significantly decreases the number of intracellular amastigotes per macrophage, percentage of macrophage infectivity and infectivity index.
- Tahghighi, Azar,Razmi, Sepideh,Mahdavi, Mohammad,Foroumadi, Parham,Ardestani, Sussan K.,Emami, Saeed,Kobarfard, Farzad,Dastmalchi, Siavoush,Shafiee, Abbas,Foroumadi, Alireza
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experimental part
p. 124 - 128
(2012/07/03)
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- Fast and reliable method for the preparation of ortho- and para-[ 18F]fluorobenzyl halide derivatives: Key intermediates for the preparation of no-carrier-added PET aromatic radiopharmaceuticals
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A fast and reliable method suitable for the automated preparation of (substituted) [18F]fluorobenzyl halides from several [ 18F]fluorobenzaldehydes was developed. Aromatic nucleophilic substitution of trimethylammonium benzaldehyde t
- Lemaire, Christian,Libert, Lionel,Plenevaux, Alain,Aerts, Jo?l,Franci, Xavier,Luxen, André
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experimental part
p. 48 - 55
(2012/06/18)
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- PALLADIUM-CATALYZED ORTHO-FLUORINATION
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A new method of ortho-fluorination where an aryl C—H bond is directly replaced by an aryl C-F bond in a palladium-catalyzed reaction is provided. The method includes the ortho-fluorination of a triflamide protected benzylamine, a palladium catalyst, such as Pd(OTf)2, a fluorinating reagent such as N-fluoro-2,4,6-trimethylpyridinium triflate, and a ligand to promote the reaction such as N-methylpyrrolidinone (NMP).
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- Novel purine-based fluoroaryl-1,2,3-triazoles as neuroprotecting agents: Synthesis, neuronal cell culture investigations, and CDK5 docking studies
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A series of novel purine-based fluoroaryl triazoles were synthesized using the Cu(I) catalyzed 1,3-dipolar cycloaddition reactions (click reactions), and assayed for their neuroprotective effects using fluorescence electron microscopy. Among these triazoles, o-fluorophenylmetyl-triazole, 7, has comparable neuroprotective effect as that of Flavopiridol (1) and Roscovitine (2), the state of the art CDK inhibitors, against the Aβ induced neurotoxicity. These results are substantiated using computer docking methods (DarwinDock/GenDock), which predict that Roscovitine and the triazole 7 bind to the ATP-binding site of CDK5/p25 with comparable binding energies, whereas the corresponding pentafluorophenylmethyl-triazole, 9, has dramatically reduced binding energy (in accordance with its lack of neuroprotection). These combined experimental and theoretical studies support the involvement of CDK5/p25 in the neuronal cell cycle re-entry.
- Nair, Nanditha,Kudo, Wataru,Smith, Mark A.,Abrol, Ravinder,Goddard III, William A.,Reddy, V. Prakash
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supporting information; experimental part
p. 3957 - 3961
(2011/08/06)
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- Design synthesis and biological evaluation of 3-substituted triazole derivatives
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Based on the active site of lanosterol 14α-demethylase of azole antifungal agents, sixteen 1-(1H-1,2,4-triazole-1-yl)- 2-(2,4-difluorophenyl)-3- (N-n-butyl-N-1-substitutedbenzyl-4-methylene-1H-1,2,3-triazole)-2-propanols have been designed, synthesized and evaluated as antifungal agents. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that some of the compounds exhibited excellent activities with broad spectrum.
- Wang, Bao Gang,Yu, Shi Chong,Chai, Xiao Yun,Yan, Yong Zheng,Hu, Hong Gang,Wu, Qiu Ye
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scheme or table
p. 519 - 522
(2012/01/05)
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- Versatile Pd(OTf)2·2H2O-catalyzed ortho-fluorination using NMP as a promoter
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(Chemical Equation Presented) Pd(OTf)2·2H 2O-catalyzed ortho-fluorination of triflamide-protected benzylamines is reported. The use of N-fluoro-2,4,6-trimethylpyridinium triflate as the F+ source and NMP as a promoter is crucial for this reaction. The conversion of triflamide into a wide range of synthetically useful functional groups makes this fluorination protocol broadly applicable in medicinal chemistry and synthesis.
- Wang, Xisheng,Mei, Tian-Sheng,Yu, Jin-Quan
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supporting information; experimental part
p. 7520 - 7521
(2009/10/17)
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