Triazolyl Moiety Research Articles

Synthetic Strategies to Prepare Bioactive Lysine and Peptide Conjugates With Triazolium Derivatives

AbstractPeptides conjugated with organic molecules can be useful tools for the development of novel bioactive compounds. The lysine side‐chain is an interesting functional group to act as a linker to connect small molecules in peptide conjugates. Herein we present the design and synthesis of four Safirinium derivatives, their facile conjugation to lysine in solid phase, and incorporation in peptides. The compounds differing in the functionalization of nitrogen N2 of the condensed triazolyl moiety are novel building blocks to design conjugates to perform structure‐activity relationship studies of elastase inhibitors. Consequently, structural investigations of the lysine building blocks and of the corresponding peptide conjugates were performed. We present herein the potential of the Safirinium analogs to act as elastase inhibitors in assays performed on porcine pancreas elastase.

Electrocatalytic hydrogen evolution by Co(II) complexes of bistriazolylpyridines

Two cobalt complexes [Co(L1)2](ClO4)2⋅4CH3CN (1) and [Co(L2)2](ClO4)2⋅2CH3CN⋅0.5H2O (2) of the new click-derived bistriazolylpyridines 2,6-bis(1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)isonicotinate methyl ester (L1) and 2,6-bis-(1-methoxycarbonylmethyl-1H-1,2,3-triazol-4-yl)isonicotinate methyl ester (L2) were synthesized and characterized. The electrocatalytic hydrogen evolution reaction (HER) mediated by complexes 1 and 2 was studied in CH3CN in the presence of acetic acid. Both complexes catalyzed HER with low overpotentials and high Faradaic efficiencies (370 mV and 93% for 1, 300 mV and 95% for 2). The distal substituents on the triazolyl moiety of the bistriazolylpyridines have apparent impacts on the redox and catalytic properties of 1 and 2. The catalytic behaviors were further studied using spectroelectrochemistry and the reductant cobaltocene. It was found that the reduction of the bistriazolylpyridines was necessary for the catalytic activity. Plausible pathways were proposed for the HER mediated by 1 and 2. This work provided some hints for the preparation of HER catalysts based on the redox-active triazolylpyridine ligands.

Design, Preparation, Characterization and Evaluation of Five Cocrystal Hydrates of Fluconazole with Hydroxybenzoic Acids.

To modulate the physicochemical properties of fluconazole (FLZ), a multifunctional antifungal drug, the crystal engineering technique was employed. In this paper, five novel cocrystal hydrates of FLZ with a range of phenolic acids from the GRAS list, namely, 2,4-dihydroxybenzoic acid (24DHB), 3,4-dihydroxybenzoic acid (34DHB, form I and form II), 3,5-dihydroxybenzoic acid (35DHB), and 3,4,5-trihydroxybenzoic acid (345THB) were disclosed and reported for the first time. Crystals of these five hydrates were all obtained for single-crystal X-ray diffraction (SCXRD) analysis. Robust (hydroxyl/carboxyl) O-H. . . Narom hydrogen bonds between acids and FLZ triazolyl moiety were observed to be dominant in guiding these crystal forms. The water molecule plays the role of supramolecular "linkage" in the strengthening and stabilization of these hydrates by interacting with FLZ and acids through O-H. . . O hydrogen bonds. In particular, the formation of FLZ-34DHB-H2O (1:1:1) significantly reduces hygroscopicity and hence improves the stability of FLZ, the latter of which is unstable and easily transforms into its monohydrate form. Increased initial dissolution rates were observed in the obtained cocrystal forms, and an enhanced intrinsic dissolution rate was obtained in FLZ-35DHB-H2O (1:1:1) in comparison with commercialized FLZ form II.

1,2-Acyl migration with α-imino rhodium carbenoids leading to substituted 1-naphthols.

A unique method for the synthesis of substituted 1-naphthols by a rhodium(II)-catalysed ring-expansion reaction of 2-triazolyl-1-indanone derivatives is reported. 1,2-Acyl migration occurs with an intermediate α-imino rhodium carbenoid generated from the triazolyl moiety.

Triazolyl-Functionalized N-Heterocyclic Carbene Half-Sandwich Compounds: Coordination Mode, Reactivity and in vitro Anticancer Activity.

We report investigations on the anticancer activity of organometallic [MII/III (η6 -p-cymene/η5 -pentamethylcyclopentadienyl)] (M=Ru, Os, Rh, and Ir) complexes of N-heterocyclic carbenes (NHCs) substituted with a triazolyl moiety. Depending on the precursors, the NHC ligands displayed either mono- or bidentate coordination via the NHC carbon atom or as N,C-donors. The metal complexes were investigated for their stability in aqueous solution, with the interpretation supported by density functional theory calculations, and reactivity to biomolecules. In vitro cytotoxicity studies suggested that the nature of both the metal center and the lipophilicity of the ligand determine the biological properties of this class of compounds. The IrIII complex 5 d bearing a benzimidazole-derived ligand was the most cytotoxic with an IC50 value of 10 μM against NCI-H460 non-small cell lung carcinoma cells. Cell uptake and distribution studies using X-ray fluorescence microscopy revealed localization of 5 d in the cytoplasm of cancer cells.

Triazole-Modified Peptidomimetics: An Opportunity for Drug Discovery and Development.

Peptidomimetics play a fundamental role in drug design due to their preferential properties regarding natural peptides. In particular, compounds possessing nitrogen-containing heterocycles have been intensively studied in recent years. The triazolyl moiety incorporation decreases the molecule susceptibility to enzymatic degradation, reduction, hydrolysis, and oxidation. In fact, peptides containing triazole rings are a typical example of peptidomimetics. They have all the advantages over classic peptides. Both efficient synthetic methods and biological activity make these systems an interesting and promising object of research. Peptide triazole derivatives display a diversity of biological properties and can be obtained via numerous synthetic strategies. In this review, we have highlighted the importance of the triazole-modified peptidomimetics in the field of drug design. We present an overview on new achievements in triazolyl-containing peptidomimetics synthesis and their biological activity as inhibitors of enzymes or against cancer, viruses, bacteria, or fungi. The relevance of above-mentioned compounds was confirmed by their comparison with unmodified peptides.

Synthesis of triazole-functionalized diblock copolymers as templates for porous materials

A versatile approach towards porous polystyrene-based frameworks functionalized with triazolyl moieties is reported. These porous materials were prepared from poly(D,L-lactic acid)-block-poly(styrene-stat-4-azidomethylstyrene) (PLA-b-P(S-stat-4-AMS)) diblock copolymer precursors. Upon macroscopic orientation and subsequent alkaline hydrolysis of the PLA block, such triazolyl-containing porous polystyrenes were produced. Experimentally, a PLA macroinitiator was synthesized by ring-opening polymerization (ROP) of D,l-lactide using a heterobifunctional initiator. The prepared macroinitiator containing a terminal tertiary α-bromo ester group allowed for further ATRP statistical copolymerization of styrene and 4-azidomethylstyrene, affording the second block, i.e. the P(S-stat-4-AMS) block. The styrene to 4-azidomethylstyrene molar ratio was tuned to obtain various compositions of the hydrophobic block. PLA macroinitiators and corresponding PLA-b-P(S-stat-4-AMS) diblock copolymers were fully characterized by size exclusion chromatography (SEC), 1H and 13C nuclear magnetic resonance (NMR), Fourier Transform Infrared (FT-IR) spectroscopy, and differential scanning calorimetry (DSC). Functionalization of PLA-b-P(S-stat-4-AMS) diblock copolymers with p-tolylacetylene or 2-methyl-3-butyn-2-ol was carried out via copper-catalyzed azide-alkyne cycloaddition (CuAAC), yielding triazole ring in high yields (>90%). Finally, the porous structure of such functional polystyrene frameworks was examined by scanning electron microscopy (SEM).

Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2.

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.

Exceptionally effective generation of singlet oxygen in aqueous media via iodinated zinc-phthalocyanine

Asymmetrically substituted zinc phthalocyanine (Pc) derivatives bearing quaternized triazolyl moieties for water solubility and iodine as a heavy metal atom have been investigated as singlet oxygen generators in aqueous media. In addition to the heavy atom effect exerted by iodine covalently bonded to the Pc molecule, a second dimensional effect induced by aggregation which brings the iodine anions of triazolyl units into closer proximity to the Pc core leading to the highest reported singlet oxygen generation for a Pc derivative in water (ΦΔ = 0.87).

Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their β-adrenoceptor blocking property.

The design, synthesis, antinociceptive and β-adrenoceptor blocking activities of several eugenyloxy propanol azole derivatives have been described. In this synthesis, the reaction of eugenol with epichlorohydrin provided adducts 3 and 4 which were N-alkylated by diverse azoles to obtain the eugenyloxy propanol azole analogues in good yields. Adducts 3 and 4 were also reacted with azide ion to obtain the corresponding azide 6. The 'Click' Huisgen cycloaddition reaction of 6 with diverse alkynes afforded the title compounds in good yields. The synthesized eugenyloxy propanol azole derivatives were in vivo studied for the acute antinociception on male Spargue Dawley rats using tail-flick test. Compounds 5f, 5g, 7b and 11a exhibited potent analgesic properties in comparison with eugenol as a standard drug. In addition, all compounds were ex vivo tested for β-adrenoceptor blocking properties on isolated left atrium of male rats which exhibited partial antagonist or agonist behaviour compared to the standard drugs. The molecular docking study on the binding site of transient receptor potential vanilloid subtype 1 (TRPV1) has indicated that like capsaicin, eugenyloxy propanol azole analogues exhibited the strong affinity to bind at site of TPRV1 in a "tail-up, head-down" conformation and the presence of triazolyl moieties has played undeniable role in durable binding of these ligands to TRPV1. The in silico pharmacokinetic profile, drug likeness and toxicity predictions carried out for all compounds determined that 5g can be considered as potential antinociceptive drug candidate for future research.

Double-Strand DNA Breaks Induced by Paracyclophane Gold(I) Complexes.

Gold(I) complexes of ClickPhos [2.2]paracyclophane ligands were synthesized in excellent yields and fully characterized by spectroscopic methods as well as X-ray crystallography. The complexes exhibit a rigid ligand backbone and a triazolyl moiety and were systematically studied with respect to their cytotoxic properties. In combination with the ionic complex [(GemPhos)Au(tht)][ClO4 ] (tht=tetrahydrothiophene), in which the gold(I) atom exhibits a distorted trigonal coordination sphere of two phosphines and a labile tht ligand, their efficiency in cytotoxicity was investigated in HeLa, MCF7, and HCT116 cells as well as in a zebrafish model. Their cytotoxicity and their mechanisms of action are different and involve apoptosis, necrosis, and DNA damage. The compounds presented herein are potent metal-based cytostatics displaying LD50 values from 3.5-38 μm in different tumor cell lines and induce double-strand DNA breaks (DSB) as shown by H2AX phosphorylation (γH2AX) at foci of DSBs.

Rhenium Complexes Based on an N2O Tridentate Click Scaffold: From Synthesis, Structural and Theoretical Characterization to a Radiolabelling Study

A general synthetic approach to a novel range of semirigid bifunctional chelating agents (BCAs) that include an aromatic ring and a triazolyl moiety in the chelating unit has been investigated for the fac‐[M(CO)3]+ core (M = 185/187Re or 188Re). The strategy includes the facile preparation of these N2O ligands bearing various functionalized arms (carboxylate, terminal alkyne, aromatic amine). The reaction of commercial [Re(CO)5Cl] {or a freshly prepared [Re(OH2)3(CO)3]+ precursor} with our BCAs in methanol led to the formation of stable neutral tricarbonylrhenium complexes of general formula [Re(CO)3(L)] (LH = 5, 10, 11) in high yields. These compounds were characterized by IR and NMR spectroscopy, mass spectrometry, electrochemistry, and X‐ray crystallography for [Re(CO)3(5–H)] and [Re(CO)3(11–H)] as well as by DFT calculations. The analogous rhenium‐188 complexes [188Re(CO)3(5)] and [188Re(CO)3(11–H)] were also prepared, in acceptable to excellent yields, by the reaction of 5 or 11 with the fac‐[188Re(OH2)3(CO)3]+ precursor in methanol at 80 °C. The structural identities of the radioactive complexes were assessed by HPLC studies. The good affinity of these click ligands for the ReI core combined with the ease of their derivatization make this chelating system promising for the conception of target‐specific radiopharmaceuticals for therapeutic purposes.

The hydridotris(3-nitro-1,2,4-triazol-1-yl)borate, a new nitro-substituted electron withdrawing polydentate “scorpionate”-type ligand and related copper and silver phosphane complexes

The new tripodal “scorpionate”-type ligand, the sodium hydridotris(3-nitro-1,2,4-triazol-1-yl)borate Na[HB(tzNO2)3] (1), containing electron withdrawing nitro functional groups on the azolyl moiety, has been synthesized in high yield starting from 3-nitro-1,2,4-triazole and sodium borohydride. New copper(I) and silver(I) complexes, [HB(tzNO2)3]M(PR3)2 (M=Cu or Ag; PR3=P(C6H5)3, or P(p-C6H4CH3)3) have been synthesized from the reaction of CuCl or AgNO3 with Na[HB(tzNO2)3] and triphenylphosphane or tri(p-tolyl)phosphane, respectively. These compounds have been characterized by elemental analyses, FT-IR, ESI-MS and multinuclear NMR spectroscopy. X-ray crystal structure of Na[HB(tzNO2)3] (1) shows that it has polymeric network structure resulting from sodium atoms of tripodal Na[HB(tzNO2)3] forming inter-molecular Na–N bonds to three nitrogen atoms of three neighboring triazolyl moieties of Na[HB(tzNO2)3]. Each sodium center has distorted octahedral geometry with three short Na–N (inter-molecular) and three long Na–N bonds (to chelating N-atoms of [HB(tzNO2)3]- ligand). This nitro-substituted scorpionate ligand could be of interest due to its high coordinative flexibility from endo- to exo-polydentate coordination mode.

Synthesis, photophysical properties of triazolyl-donor/acceptor chromophores decorated unnatural amino acids: Incorporation of a pair into Leu-enkephalin peptide and application of triazolylperylene amino acid in sensing BSA

The research in the field of design and synthesis of unnatural amino acids is growing at a fast space for the increasing demand of proteins of potential therapeutics and many other diversified novel functional applications. Thus, we report herein the design and synthesis of microenvironment sensitive fluorescent triazolyl unnatural amino acids (UNAA) decorated with donor and/or acceptor aromatic chromophores via click chemistry. The synthesized fluorescent amino acids show interesting solvatochromic characteristic and/or intramolecular charge transfer (ICT) feature as is revealed from the UV–visible, fluorescence photophysical properties and DFT/TDDFT calculation. HOMO–LUMO distribution shows that the emissive states of some of the amino acids are characterized with more significant electron redistribution between the triazolyl moiety and the aromatic chromophores linked to it leading to modulated emission property. A pair of donor–acceptor amino acid shows interesting photophysical interaction property indicating a FRET quenching event. Furthermore, one of the amino acid, triazolyl-perylene amino acid, has been exploited for studying interaction with BSA and found that it is able to sense BSA with an enhancement of fluorescence intensity. Finally, we incorporated a pair of donor/acceptor amino acids into a Leu-enkephalin analogue pentapeptide which was found to adopt predominantly type II β-turn conformation. We envisage that our investigation is of importance for the development of new fluorescent donor–acceptor unnatural amino acids a pair of which can be exploited for generating fluorescent peptidomimetic probe of interesting photophysical property for applications in studying peptide–protein interaction.

1,4-disubstituted-[1,2,3]triazolyl-containing analogues of MT-II: design, synthesis, conformational analysis, and biological activity.

Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The CuI-catalyzed azide–alkyne 1,3-dipolar Huisgen’s cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-to-side chain cyclization. In fact, the proteolytic stable 1,4- or 4,1-disubstituted [1,2,3]triazolyl moiety is isosteric with the peptide bond and can function as a surrogate of the classical side chain-to-side chain lactam forming bridge. Herein we report the design, synthesis, conformational analysis, and functional biological activity of a series of i-to-i+5 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp5 to Lys10 side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors.

Synthesis and Reactivity of Heteroditopic Dicarbene Rhodium(I) and Iridium(I) Complexes Bearing Chelating 1,2,3-Triazolylidene–Imidazolylidene Ligands

1,2,3-Triazol-5-ylidenes (tzNHC) have become a popular class of NHC ligands in homogeneous catalysis. Herein, we introduce chelate monovalent Rh- and Ir(cod) complexes bearing bidentate ligands that combine this tzNHC and an Arduengo-type NHC motif. The reactivity of these complexes with H2 and CO gas has been investigated, leading to an interesting octahedral [Ir(tzNHC-CH2-NHC)(CO)2(H)2]OTf complex and [M(tzNHC-CH2-NHC)(CO)2]OTf complexes. The carbonyl stretching frequencies of the latter indicate that the ligand has stronger electron-donating properties than classic di-NHC ligands. The square planar rhodium and iridium NHC-tzNHC complexes have been applied in transfer hydrogenation employing isopropyl alcohol as the hydrogen donor, in which they show moderate activity (Ir > Rh) toward a range of ketones as well as for an aldehyde, an imine, and a diene. The new dicarbene complexes proved to be more active for this reaction than the analogues in which the triazolyl moiety coordinates through a nitrogen donor.

Novel triazole alcohol antifungals derived from fluconazole: design, synthesis, and biological activity.

A series of new triazole alcohol antifungals were designed by replacing one of the triazolyl moiety from fluconazole with a distinct 4-amino-3-mercapto-1,2,4-triazole motif, which is found in some antimicrobial agents. The antimicrobial susceptibility testing of target compounds demonstrated that the direct analogs of fluconazole (difluorophenethyl-triazoles) were less active against fungi, while compound 10h containing dichloro substitutions on both phenyl rings of the molecule had potent activity against yeasts including Candida albicans (four strains) and Cryptococcus neoformans (MICs = 2-8 μg/mL). Also, compound 10h was active against Candida parapsilosis, Epidermophyton floccosum, and Trichophyton mentagrophytes, while it showed no activity against Gram-positive and Gram-negative bacteria. Finally, a molecular docking study suggested that compound 10h interacts suitably with lanosterol 14α-demethylase, which is the key enzyme in ergosterol biosynthesis.

ChemInform Abstract: 6‐Triazolyl‐Substituted Sulfocoumarins Are Potent, Selective Inhibitors of the Tumor‐Associated Carbonic Anhydrases IX and XII.

AbstractA variety of 6‐substituted sulfocoumarins incorporating triazolyl moieties are synthesized by employing click chemistry.

Solid-Phase Synthesis of Cyclic Lipopeptidotriazoles

The solid-phase synthesis of cyclic lipopeptidotriazoles derived from the cyclic decapeptide c(Lys-Lys2-Leu-Lys-Lys5-Phe-Lys-Lys-Leu-Gln) (BPC194), incorporating a triazolyl ring at Lys2 and a hexanoyl group at Lys5, was studied. Four different strategies that required the use of five orthogonal protecting groups (Fmoc, tBu, All, pNZ, ivDde) were explored. The influence of the side-chain protection of Lys2 and Lys5 with the ivDde and pNZ groups was evaluated by incorporating Lys2(ivDde)/Lys5(pNZ) or Lys2(pNZ)/Lys5(ivDde). The order of removal of these protecting groups and of the introduction of the hexanoyl and triazolyl moieties was also studied. The best strategy included: (i) synthesis of a cyclic peptidyl resin bearing Lys2(ivDde) and Lys5(pNZ); (ii) pNZ group removal; (iii) acylation with hexanoic acid; (iv) ivDde group removal; and (v) acylation with propiolic acid followed by an azide–alkyne 1,3-dipolar cycloaddition. By using this protocol, a set of cyclic lipopeptidotriazoles was prepared in high purities.

Synthesis of novel 1,2,3-triazolyl derivatives of pregnane, androstane and D-homoandrostane. Tandem "click" reaction/Cu-catalyzed D-homo rearrangement.

Copper-catalyzed 1,3-dipolar cycloaddition has been employed in the reaction of steroidal azides with various terminal alkynes. A number of novel 1,2,3-triazolyl derivatives of pregnane, androstane and D-homoandrostane were obtained in high yield (70-98%). The developed synthetic protocols allowed us to attach the triazolyl moiety to both the side chain and the steroidal backbone directly, despite the steric hindrance exerted by the polycyclic system. The presence of Cu(II) was shown to evoke d-homo rearrangement under mild conditions. A rational choice of the copper precatalyst permitted us to carry out the "click" reaction either along with tandem d-homo rearrangement or in the absence of this process. The tendency of 16-heterosubstituted steroids to undergo D-homo rearrangement under Cu(II) catalysis was studied.