Triazole Moiety Research Articles

Synthesis and bioassay of a new class of disubstituted 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles

A new class of aroylethenesulfonylmethyl styryl oxadiazoles/thiadiazoles/triazoles and arylsulfonylethenesulfonylmethyl styryl oxadiazoles/thiadiazoles/triazoles were synthesized from the synthetic intermediates E-aroylethenesulfonylacetic acid methyl ester, E-arylsulfonylethenesulfonylacetic acid methyl ester and substituted cinnamic acids adopting conventional and ultrasonication methodologies. All the synthesized compounds were obtained in higher yields and in shorter reaction times in ultrasound irradiation method when compared with conventional method. The structures of all the compounds were characterized by IR, 1H NMR, 13C NMR and mass spectra. All the title compounds were tested for antimicrobial activity. The arylsulfonylethenesulfonylmethyl styryl azoles displayed higher antimicrobial activity than the aroylethenesulfonylmethyl styryl azoles. The compounds having triazole moiety showed greater activity than those with oxadiazole and thiadiazole. Amongst all the tested compounds unsubstituted and chloro substituted arylsulfonylethenesulfonyl methyl styryl triazoles are identified as potential antimicrobial agents particularly against B. subtilis and P.chrysogenum.

Synthesis of (1S)-(+)-camphor-10-sulfonic acid derivatives and investigations in vitro and in silico of their antiviral activity as the inhibitors of fi lovirus infections

N-Heterocycle-containing (1S)-(+)-camphor-10-sulfonamide derivatives were synthesized. Their antiviral activity against the Ebola and Marburg viruses was estimated using a pseudovirus system based on the vesicular stomatitis virus. The derivatives bearing morpholine and triazole moieties demonstrated the highest inhibitory activity towards the Ebola virus glycoprotein. A moderate activity against the Marburg virus was found for a compound containing the piperidine moiety. A molecular modeling of the interaction between the synthesized derivatives and the binding site of glycoprotein of the Ebola virus was performed.

In‐situ Robust Polymeric Networks Prepared via Facile Uncatalyzed Huisgen Cycloaddition of Alkyne‐terminated Polyurethane with Terminal Azides

AbstractWe carried out catalyst – and solvent‐free Huisgen azide‐alkyne cycloadditon (AAC) to develop the polyurethane‐based networks crosslinked through triazole moieties at chain‐ends. An asymmetrical divalent compound carrying the hydroxyl and electron‐deficient alkyne as terminal groups was newly synthesized to prepare the alkyne‐terminated polymer containing urethane moieties within polymer backbone. Additionally, three kinds of terminal‐azide crosslinkers were introduced to react with alkyne‐terminated polyurethanes without any promoters. Kinetics of the uncatalyzed AAC were monitored by using real‐time FT‐IR technique at 50 °C temperature. The rate of AAC using aromatic azide dipole was faster than other dipoles. Compared to the non‐polyurethane‐based networks crosslinked via either urethane or triazole moieties at chain‐ends, triazole chain‐ends crosslinked polyurethane networks conveyed the excellent mechanical properties. However, thermal properties at low temperature were not as good as those of non‐polyurethane networks. Especially, Tg of polyurethane networks formed by an oligomeric azide crosslinker was much higher than others.

Effect of Triazole-Modified Thymidines on DNA and RNA Duplex Stability

Previous reports showed that consecutive incorporations of triazole-modified 2′-deoxyuridines stabilized DNA·DNA and DNA·RNA duplexes due to additional π-stacking between triazole moieties. In this...

Synthesis, biological activity and multiscale molecular modeling studies of bis-coumarins as selective carbonic anhydrase IX and XII inhibitors with effective cytotoxicity against hepatocellular carcinoma

A series of novel bis-coumarin derivatives containing triazole moiety as a linker between the alkyl chains was synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms I, II, IX and XII were evaluated. In addition, cytotoxic effects of the synthesized compounds on renal adenocarcinoma (769P), hepatocellular carcinoma (HepG2) and breast adeno carcinoma (MDA-MB-231) cell lines were examined. While the hCA I and II isoforms were inhibited in the micromolar range, the tumor-associated isoform hCA IX and XII were inhibited in the high nanomolar range. 4-methyl-7-((1-(12-((2-oxo-2H-chromen-7-yl)oxy)dodecyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (5p) showed the strongest inhibitory activity against hCA IX with the Ki of 144.6 nM and 4-methyl-7-((1-(10-((2-oxo-2H-chromen-7-yl)oxy)decyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (5n) exhibited the highest hCA XII inhibition with the Ki of 71.5 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modelling approaches were applied. Low energy docking poses of studied molecules at the binding sites of targets have been predicted. In addition, electrostatic potential surfaces (ESP) for binding sites were also generated to understand interactions between proteins and active ligands.

Efficient Synthesis of Some New 1,3,4‐Thiadiazoles and 1,2,4‐Triazoles Linked to Pyrazolylcoumarin Ring System as Potent 5α‐Reductase Inhibitors

The current study in this article concerned with construction of five‐membered heterocycles with multiple heteroatoms as nitrogen and sulfur from readily available starting materials and reagents. Treatment of 1‐(2‐oxo‐2H‐chromene‐3‐carbonyl)‐3‐phenyl‐1H‐pyrazol‐5(4H)‐one with each of phenylisothiocyanate in alcoholic potassium hydroxide and carbon disulfide in basic medium gave rise to a thioanilide and methylthio derivatives, respectively. Treatment of the latter compounds with a variety of hydrazonoyl halides resulted in construction of thiadiazole moiety linked to pyrazole ring. Furthermore, triazole derivatives were synthesized from the thioanilide derivative through its reaction with methyl iodide followed by reaction with hydrazonoyl halides. 5α‐Reductase inhibition activity for the prepared compounds was investigated against the reference drug anastrozole, and the results showed that the inhibition activity of compounds 5g and 11g is more potent than anastrozole. Also compounds bearing triazole moiety is more potent than compounds bearing thiadiazole one. Moreover, the anti‐prostate cancer screening anti‐androgenic bioassay in human prostate cancer cells for the tested compounds was evaluated, and the results showed great inhibition growth and potential antiandrogens.

Concentration and Recovery of Dyes from Textile Wastewater Using a Self-Standing, Support-Free Forward Osmosis Membrane.

Forward osmosis (FO) can potentially treat textile wastewaters with less fouling than pressure-driven membrane processes such as reverse osmosis and nanofiltration. However, conventional FO membranes with asymmetric architecture experience severe flux decline caused by internal concentration polarization and fouling as dye molecules accumulate on the membrane surface. In this study, we present a new strategy for concentrating dye by using a self-standing, support-free FO membrane with a symmetric structure. The membrane was fabricated by a facile solution-casting approach based on a poly(triazole- co-oxadiazole- co-hydrazine) (PTAODH) skeleton. Due to its dense architecture, ultrasmooth surface, and high negative surface charge, the PTAODH membrane exhibits excellent FO performance with minimal fouling, low reverse salt flux, and negligible dye passage to the draw solution side. Cleaning with a 40% alcohol solution, after achieving a concentration factor of ∼10, resulted in high flux recovery ratio (98.7%) for the PTAODH membrane, whereas significant damage to the active layers of two commercial FO membranes was observed. Moreover, due to the existence of cytotoxic oxadiazole and triazole moieties in the polymer structure, our PTAODH membrane exhibited an outstanding antibacterial property with two model bacteria. Our results demonstrate the promising application of the symmetric PTAODH membrane for the concentration of textile wastewaters and its superior antifouling performance compared to state-of-the-art commercial FO membranes.

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines.

The synthesis of novel fluorescent N(9)-alkylated 2-amino-6-triazolylpurine and 7-deazapurine derivatives is described. A new C(2)-regioselectivity in the nucleophilic aromatic substitution reactions of 9-alkylated-2,6-diazidopurines and 7-deazapurines with secondary amines has been disclosed. The obtained intermediates, 9-alkylated-2-amino-6-azido-(7-deaza)purines, were transformed into the title compounds by CuAAC reaction. The designed compounds belong to the push–pull systems and possess promising fluorescence properties with quantum yields in the range from 28% to 60% in acetonitrile solution. Due to electron-withdrawing properties of purine and 7-deazapurine heterocycles, which were additionally extended by triazole moieties, the compounds with electron-donating groups showed intramolecular charge transfer character (ICT/TICT) of the excited states which was proved by solvatochromic dynamics and supported by DFT calculations. In the 7-deazapurine series this led to increased fluorescence quantum yield (74%) in THF solution. The compounds exhibit low cytotoxicity and as such are useful for the cell labelling studies in the future.

Design and Synthesis of Triazole-Phthalimide Hybrids with Anti-inflammatory Activity.

Phthalimido-alkyl-1H-1,2,3-triazole derivatives 3a-d and 4a-d were efficiently synthesized using 1,3-dipolar cycloaddition reaction. Anti-inflammatory activity and toxicity studies were performed. The results demonstrated that all the tested compounds reduced carrageenan-induced paw edema and indicated no lethality for toxicity against Artemia salina and acute toxicity in vivo (LD50 up to 1 g kg -1). Furthermore, the structure of phthalimide linked to phenyl group proved to be more active than the compounds containing benzothiazole moiety. Structural modifications such as removal of the phthalimide group and subsequent acetylation, to exemplify a non-cyclic amide, demonstrate that the phthalimide and triazole moieties are important for design of potent candidates with anti-inflammatory drug proprieties. Docking into the cyclooxygenase-2 (COX-2) confirms the importance of the phthalimide and triazole groups in the anti-inflammatory activity. The histopathological studies showed that the compounds 3a-d and 4a-d did not cause serious pathological lesions liver or kidneys.

Insights into the nature of weak noncovalent interactions in 3-(4-fluorophenyl)-6-(2-fluorophenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole, a potential bioactive agent: X-ray, QTAIM and molecular docking analysis

A thorough examination of weak interactions present in the crystal structure of the title compound was investigated. Intramolecular CH⋯N and F⋯S interactions make the molecule as fused 6,5,5,5,6,6-membered ring system. Two of the closely related structures show 1D-isostructurality with the title compound. The crystal structure is stabilized by different types of weak intermolecular CH⋯N, CH⋯F, CH···π and S···π and π···π interactions. The first two strongest dimers are stabilized by stacking interactions. The nature of these interactions and their role was established through quantum theory of atoms-in-molecules approach. The Hirshfeld surface analysis clearly reveals that the para-substituted fluorine substantially change the contribution of intermolecular H⋯H and H⋯C contacts. The molecular docking analysis suggests that the title compound shows anti-inflammatory activity and selective against cyclooxygenase-1 (COX-1) enzyme and the 2-fluorophenyl and triazole moieties of the title compound are involved in the π···π interactions with active site aromatic residues.

COX-1/COX-2 inhibition assays and histopathological study of the new designed anti-inflammatory agent with a pyrazolopyrimidine core

Four pyrazolopyrimidine series were prepared with a substitution at position- 4 by Schiff base, triazole, oxadiazole and pyrazole moieties (7a-f, 8a,b, 9a-f, 10a,b and 13a,b), respectively. All the synthesized compounds were evaluated in vitro against COX-2 and in vivo against carrageenan-induced rat paw edema as anti-inflammatory agents. Regarding the anti-inflammatory activity (AI) compounds 7c, 7f, 8a, and 9a showed higher activity with respect to celecoxib. Compounds 9a, 7d, and 7f were closely selective to celecoxib. Also, 7c and 7d were safer than indomethacin and similar to celecoxib as resulted from the histopathological study. In addition, the docking study that showed the binding mode of prominent pyrazolopyrimidine compounds inside the COX-2 receptor. Formation of unexpected pyrazole 13a and 13b was briefly discussed using 2D NMR.

Thiol-Cyanobenzothiazole Ligation for the Efficient Preparation of Peptide-PNA Conjugates.

Antisense oligonucleotide (ASO)-based drugs are emerging with great potential as therapeutic compounds for diseases with unmet medical needs. However, for ASOs to be effective as clinical entities, they should reach their intracellular RNA and DNA targets at pharmacologically relevant concentrations. Over the past decades, various covalently attached delivery vehicles have been utilized for intracellular delivery of ASOs. One such approach is the use of biocompatible cell-penetrating peptides (CPPs) covalently conjugated to ASOs. The stability of the linkage is of paramount importance for maximal intracellular delivery to achieve the desired therapeutic effect. In this study, we have investigated the efficiency and stability of four different bioorthogonal and nonreductive linkages including triazole, thioether, thiosuccinimide thioether and thiazole moieties. Here we have shown that thiazole and thiosuccinimide are the two most efficient and facile approaches for the preparation of peptide-ASO conjugates. The thiazole linkage had a higher stability compared to the thiosuccinimide thioether at physiological conditions (pH 7.4, 37 °C) in the presence of a biologically relevant concentration of glutathione. We have also shown that the peptide-ASO conjugate with a thiosuccinimide linkage has a significantly lower antisense activity compared to the peptide-ASO with the thiazole linkage, which maintains its antisense activity after 24 h of exposure to glutathione. In summary, we have demonstrated that the bioorthogonal thiazole linkage offers the benefits of mild reaction conditions, fast reaction kinetics, absence of any byproducts, and higher stability compared to other conjugation approaches. This facile ligation can be used for the synthesis of a variety of bioconjugates where a stable linkage is required.

Water-Assisted Self-Aggregation of Benzimidazole and Triazole Adducts.

The manuscript revolves around an interesting observation of solidification of a solution of N-((1-((1-ethyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)aniline (A6) in the NMR tube after around 12 h. Real-time images showed fibrillar and spherulitic growth with tip branching and side branching, which is thermoreversible. The compound under investigation is unique because it is synthesized to understand the anticancer activity with two pharmacophores, benzimidazole and triazole. Click chemistry is employed for in situ generation of triazole moiety on benzimidazole. Previously, benzimidazole-based compounds have shown self-aggregation-induced gel-like behavior because of hydrogen bonding and/or π–π stacking interactions. In the present case, NMR titrations with D2O addition showed two distinct changes in the chemical shift for methylene bridges (connecting benzimidazole and triazole ring) and ortho protons of the phenyl ring (attached to triazole ring). Interestingly, a single-crystal X-ray structure shows the absence of hydrogen bonds and π–π stacking while in the presence of only two distinct close contacts, completely correlating NMR data discussed in detail. A similar “molecular origin” for self-aggregation is observed in seven other flexible but regioisomeric compounds, which were designed and synthesized for inducing hydrogen bonding through the removal of N-ethyl group and insertion of aniline and/or fluoro group.

Supramolecular nanocatalyst in water: successive click-driven assembly of click-derived rod amphiphiles

An aqueous supramolecular nanocatalyst with interfacial curvature controlled by a click reaction was developed based on the self-assembly of a rod amphiphile containing a triazole moiety that chelates CuI ions for successive and efficient click-to-click reactions.

Triazole-modified chitosan: a biomacromolecule as a new environmentally benign corrosion inhibitor for carbon steel in a hydrochloric acid solution.

In this work, a new inhibitor, triazole modified chitosan, was synthesized for the first time following chemical modification of chitosan using 4-amino-5-methyl-1,2,4-triazole-3-thiol. The newly synthesized biopolymer (CS–AMT) was characterized using FTIR and NMR, and then it was evaluated as an inhibitor against corrosion of carbon steel in 1 M hydrochloric acid. The corrosion testing and evaluation were performed thoroughly employing the weight loss method, electrochemical measurements and surface analysis. A maximum corrosion inhibition efficiency of >95% was obtained at 200 mg L−1 concentration of inhibitor. The adsorption of inhibitor obeyed the Langmuir isotherm and showed physical and chemical adsorption. The electrochemical study via impedance analysis supported the adsorption of the inhibitor on the surface of carbon steel, and the potentiodynamic polarization indicated a mixed type of inhibitor behavior with cathodic predominance. To get a better insight on the interaction of inhibitor molecules with the metal surface, a detailed theoretical study was performed using DFT calculations, Fukui indices analysis and molecular dynamics (MD) simulation. The DFT study showed a lower energy gap of CS–AMT and the MD simulations showed an increased binding energy of CS–AMT compared to the parent chitosan and triazole moieties thereby supporting the experimental findings.

Biotinylated-cationic zinc(II) phthalocyanine towards photodynamic therapy

Targeting biotin receptors in cancer cells can improve specifying of photosensitizers (PSs) for cancer treatment by photodynamic therapy (PDT) applications. Consequently, there has been extensive research focusing mainly on the design of PSs with optimized pharmaceutical properties and better targeting toward cancer cells. Herein a tailored mono-biotinylated zinc(II) phthalocyanine (Pc-1) substituted with six phenoxy-bis(triazolyl) substituents has been synthesized. This Pc-1 has been further modified to its cationic version (Pc-2) through quaternizing of the triazole moiety to gain water solubility. Both non-ionic zinc(II) phthalocyanine (Pc-1) and its cationic derivative (Pc-2) were characterized by standard spectroscopic techniques, namely; FT-IR,1H and [Formula: see text]C NMR, UV-Vis and MALDI-TOF, and by elemental analysis. The photophysical and photochemical properties were evaluated in DMSO for the non-ionic Pc-1 and in both DMSO and water for the cationic Pc-2.

Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-Toxoplasma gondii agents

Ursolic acid (UA), a plant-derived compound, has many properties beneficial to health. In the present study, we synthesised three series of novel UA derivatives and evaluated their anti-Toxoplasma gondii activity both in vitro and in vivo. Most derivatives exhibited an improved anti-T. gondii activity in vitro when compared with UA (parent compound), whereas compound 3d exhibited the most potent anti-T. gondii activity in vivo. Spiramycin served as the positive control. Additionally, determination of biochemical parameters, including the liver and spleen indexes, indicated compound 3d to effectively reduce hepatotoxicity and significantly enhance anti-oxidative effects, as compared with UA. Furthermore, our molecular docking study indicated compound 3d to possess a strong binding affinity for T. gondii calcium-dependent protein kinase 1 (TgCDPK1). Based on these findings, we conclude that compound 3d, a derivative of UA, could act as a potential inhibitor of TgCDPK1.

Novel synthesis of platinum complexes and their intracellular delivery to tumor cells by means of magnetic nanoparticles.

Platinum-based drugs are popular in clinics as chemotherapeutic agents to treat solid tumors. However, severe side effects such as nephro- and neurotoxicity impose strict dosage limitations that can lead to the development of drug resistance and tumor relapse. To overcome these issues Pt(iv) prodrugs and platinum delivery systems might represent the next generation of platinum-based drugs. In this study four novel Pt(ii) complexes (namely, PEG-Glu-Pt-EDA, PEG-Glu-Pt-DACH, PEG-Mal-Pt-EDA and PEG-Mal-Pt-DACH) were synthesized and a general strategy to covalently bind them to iron oxide nanoparticles was developed. The intracellular uptake and cell distribution studies of Pt-tethered magnetic nanoparticles on breast and ovarian cancer cell line models indicate that binding of the Pt complexes to the nanoparticles facilitates, for all the complexes, cellular internalization. Moreover, the magnetic nanoparticles (MNPs), as shown in a magnetofection experiment, enhance the uptake of MNP-Pt conjugates if a magnet is placed beneath the culture dish of tumor cells. As shown by a Pt release experiment, intranuclear platinum quantification and TEM analysis on cell sections, the presence of a pH-sensitive dicarboxylic group coordinating the Pt complex, triggers platinum dissociation from the NP surface. In addition, the triazole moiety facilitates endosomal swelling and the leakage of platinum from the endosomes with intranuclear localization of platinum release by the NPs. Finally, as assessed by MTT, caspase, calcein/ethidium bromide live/dead assays, among the four NP-Pt conjugates, the NP-Glu-Pt-EDA complex having a glutamate ring and ethylenediamine as a chelating amine group of the platinum showed higher cytotoxicity than the other three MNP-platinum conjugates.

A chiroptical nanoprobe for highly selective recognition of histidine enantiomers in aqueous media

Histidine is one of the essential amino acids in the human body, and the variation of its concentration in vivo has shown it to align with some liver and kidney diseases. In this work, a series of novel poly(2-oxazoline) derivatives bearing chiral pyrrolidine–triazole moieties in the side chain were designed and synthesized to serve as chemical sensors for histidine. The results demonstrated that the homopolymer HPOx2 is capable of selectively binding optically active histidine through nitrogen/Cu2+ coordination to form complexes exhibiting induced circular dichroism (ICD) signals with signs related to the absolute configuration of the guest compound. Interestingly, the micelle-type nanoparticles assembled from the corresponding amphiphilic copolymer (CPOx2) gave a much stronger CD response, with an intensity five times that of its small molecule- or homopolymer counterparts. The proposed method, based on the chiroptical probe, allows for enantioselective detection of histidine in aqueous media, showing potential application in the field of biomedical assay and chiral drug synthesis.

(Diacetoxyiodo)Benzene Mediated Fused 1,2,4-Triazole Derivatives: Synthetic and Medicinal Perspective

Hypervalent iodine(III) reagents are well known for the mild and highly selective oxidative chemical transformations, specifically in synthesis of a variety of heterocycles, in a facile and environmentally friendly manner. In past decades, triazole derivatives have gained much attention of the scientific community as some of the products containing triazole moiety contribute towards the development of effective chemotherapeutics. (Diacetoxyiodo)benzene, a hypervalent iodine(III) reagent has proven its significant role in synthesis of 1,2,4-triazoles, in particular, fused derivatives. This review highlights the (Diacetoxyiodo)benzene mediated developments made for the synthesis of fused 1,2,4-triazole derivatives till date. In addition, medicinal perspective of these heterocycles has also been summarized.