Design,synthesis and biological evaluation of quinazolin-4(3H)-one Schiff base conjugates as potential antiamoebic agents

In an effort to develop novel antiamoebic scaffolds having better efficacy than the standard drug metronidazole (IC₅₀ = 1.80 μM) used against Entamoeba histolytica, quinazolin-4(3H)-one Schiff base conjugates were synthesized and evaluated against HM1: IMSS strain of E. histolytica. Out of the thirteen compounds (S2-S14), six compounds (S2, S3, S4, S5, S6 and S11) were found to be better inhibitors than metronidazole and showed low cytotoxicity on HeLa cells, a cervical cancer cell line. The structure of intermediate compound S1 was confirmed by crystal structure studies.     

Synthesis of a new class of azathia crown macrocycles containing two 1,2,4-triazole or two 1,3,4-thiadiazole rings as subunits

A series of new 1,2/1,3-bis[o-(N-methylidenamino-5-aryl-3-thiol-4H-1,2,4-triazole-4-yl)phenoxy]alkane derivatives 3a-d and bis[o-(N-methylidenamino-2-thiol-1,3,4-thiadiazole-5-yl)phenoxy]alkanes 6a-c were prepared by condensation of 4-amino-5-(aroyl)-4H-1,2,4-triazole-3-thiols 2a-b or 2-amino-5-mercapto-1,3,4-thiadiazole with bis-aldehydes 1a-c. Further reaction of compounds 3a-d and 6a-c with dibromoalkanes afforded the new macrocycles 5a-f and 8a-d. The cyclization does not require high dilution techniques and provides the expected azathia macrocycles in good yields, ranging from 55% to 68%.     

Multi-gram scale mercury-free synthesis of optically pure 3,4,5-trisubstituted 1,2,4-triazoles using silver benzoate

We report a new method using silver benzoate instead of mercury salts as a key reagent for the synthesis of 3,4,5-trisubstituted 1,2,4-triazoles. This method allows the introduction of a large variety of substituents in the three positions. We demonstrated that we could introduce one chiral center without any loss of the optical purity. This method is compatible with at least multi-gram scale-up.     

Facile synthesis of 3,5-diaryl-1,2,4-triazoles via copper-catalyzed domino nucleophilic substitution/oxidative cyclization using amidines or imidates as substrates

Two methods for the synthesis of 3,5-diaryl-1,2,4-triazoles, both domino reactions, are reported. The first procedure, the Cu(OTf)₂-catalyzed reaction between two amidines using NaHCO₃ as a base, 1,10-phenanthroline as an additive and K₃[Fe(CN)₆]/atmospheric oxygen as the oxidant, delivers 3,5-diaryl-1,2,4-triazoles with yields up to 68%. The second procedure for the synthesis of 3,5-diaryl-1,2,4-triazoles with yields up to 64% rests on the Cu(OTf)₂-catalyzed reaction between two imidates and ammonium carbonate. This method features the formation of three bonds in a single synthetic step.     

A base-catalyzed, direct synthesis of 3,5-disubstituted 1,2,4-triazoles from nitriles and hydrazides

A convenient and efficient one step, base-catalyzed synthesis of 3,5-disubstituted 1,2,4-triazoles by the condensation of a nitrile and a hydrazide is presented. A diverse range of functionality and heterocycles are tolerated under the reaction conditions developed, and the reactivity of the nitrile partner is relatively insensitive to electronic effects.     

Elucidation of potential anticancer,antioxidant and antimicrobial properties of some new triazole compounds bearing pyridine-4-yl moiety and cyclobutane ring

Thiosemicarbazides (2a–e) were obtained by the interaction of pyridine-4-carboxylic acid hydrazide (1) with five different isothiocyanate (RNCS) derivatives. By addition of KOH to the reaction medium, ethyl, allyl, phenyl and benzyl, p-tolyl substituted 1,2,4-triazoles (3a–e) were obtained. 3a–e were dissolved in dry acetone containing K₂CO₃ in the presence of 2-chloro-1-(3-methyl-3- mesitylcyclobutyl) ethanone (4) to give 3,4,5-trisubstituted 1,2,4-triazole sulfanyl compounds containing a cyclobutane ring (5a–e). The structures of the final compounds were confirmed by elemental analyses, FT-IR, ¹H NMR and ¹³C NMR. Due to many activities regarding pharmacology, Compounds such as 1,2,4-triazole attract high attention in the fields of chemistry, pharmacology, and biology. All the newly synthesised compounds were screened for their Antioxidant, antimicrobial, anti-cancer activities. The measurement of the antioxidant feature of the compounds was performed by DPPH radical scavenging activity technique. It was observed that the activity of some of the compounds was close to the standard antioxidant BHT. Furthermore, the anticancer effects of compounds were investigated against HT29 human colon adenocarcinoma cells. It has been noted that all -compounds inhibited cancerous cells in a statistically significant compared to the control. For the measurement of antimicrobial activity Agar well diffusion method was preferred. For the antimicrobial study, S. aureus, E. faecalis, P. aeruginosa, E. coli, and a single fungi C. albicans have been used. They could also be stated as ATCC 29213, 29212, 27853, 2592, and 10231 respectively. The resulting range of MIC values for the chemicals was between 15.625 - >125 µM. In conclusion; all compounds have shown various and important bioactivities at different levels, such as being antioxidant, antimicrobial, and anticancer.     

Synthesis and single crystal X-ray analysis of two griseofulvin metabolites

The two phenols, 6-O-desmethyl griseofulvin and 4-O-desmethyl griseofulvin are metabolites of the antifungal drug griseofulvin. Herein, we present an improved synthesis of the 6-phenol derivative, and an unequivocal proof of both structures by single-crystal X-ray analysis.     

Synthesis,Structure, and In Vitro Anti-HIV Activity of New Pyrazole, 1,2,4-Thiadiazole,and 1,2,4-Triazole Derivatives

α,α′-Dichloroazo compounds 6 react with Lewis acid to furnish 1-(chloroalkyl)-1-aza-2-azoniaallene salts 4. The cations 4 react with acetylenes, isothiocyanates, isocyanates, and carbodiimides under [3+2]-cycloaddition. The cycloadducts undergo consecutive reactions, e.g., [1,2]-shifts of alkyl groups. The newly synthesized products were evaluated for their anti-HIV-1 and anti-HIV-2 activity in MT-4 cells.     

Stereoselective total synthesis of ieodomycin C

A concise stereoselective synthesis of the marine natural product ieodomycin C (3) has been achieved from commercially available pyridinium-1-sulfonate (8) in eight linear steps and 14% overall yield. The key synthetic steps included a B-alkyl Suzuki–Miyaura cross-coupling reaction and an Evans–Nagao acetate aldol reaction. The same synthetic sequence was used for preparing the enantiomer of ieodomycin C (3). Our efforts confirmed the structure of the antibacterial natural product 3.     

Synthesis of potential drug metabolites by a modified Udenfriend reaction

Several drugs (clozapine, chlorpromazine, imipramine, buspirone, diltiazem, and propranolol) were subjected to modified Udenfriend conditions (Fe²⁺/Mn²⁺/EDTA/ascorbic acid/O₂). From each reaction, one to four oxidation products were obtained in 1-8% overall yield. Many of these products (9 out of 14) have been reported to be metabolites of the parent drugs in vivo. The products resulted mainly from aromatic hydroxylation, and are not readily accessible by conventional synthesis. Thus, the described reaction may be useful in drug discovery whenever a facile synthetic access is more important than high yields (e.g., for a fast derivatisation of compounds or the preparation of metabolites). Poorly water-soluble compounds cannot be converted, which is an important limitation of this method.     

Synthesis and crystal structure analysis of 2-(4-methyl-2′-biphenyl)-4-amino-1,2,4-triazole-3-thiol

The bioactive compound 2-(4-methyl-2′-bip-henyl)-4-amino-1,2,4-triazole-3-thiol, F.W. 282.09 was synthesized, characterized by spectroscopic techniques and confirmed by X-ray crystal structure analysis. The title compound crystallizes in monoclinic class under the space group P2₁/c with cell parameters, a=11.273(3) Å, b=17.245(1) Å, c=7.413(1) Å, β=97.742(5)° and Z=4. The structure exhibits inter-molecular hydrogen bonding of the type N–H···S.     

Stereoselective determination of hydroxychloroquine and its metabolites in human urine by liquid-phase microextraction and CE

Liquid-phase microextraction based on polypropylene hollow fibers and CE were applied for the chiral determination of hydroxychloroquine (HCQ) and its metabolites (desethylchloroquine, DCQ; desethylhydroxychloroquine, DHCQ; bisdesethylchloroquine, BDCQ) in human urine. The analytes were extracted from 3 mL of urine spiked with the internal standard (metoprolol) and alkalinized with 250 muL of 2 M NaOH. The analytes were extracted into 1-octanol impregnated in the pores of the hollow fiber, and into an acid acceptor solution inside the hollow fiber. The electrophoretic separations were carried out in 100 mmol/L Tris buffer (pH adjusted to 9.0 with phosphoric acid) containing 1% w/v S-beta-CD and 30 mg/mL HP-beta-CD with a constant voltage of +18 kV. The method was linear over the concentration range of 10-1000 ng/mL for each HCQ stereoisomer and 21-333 ng/mL for each metabolite stereoisomer. Within-day and between-day assay precision and accuracy for the analytes were studied at three concentration levels for each stereoisomer and were lower than 15%. The developed method was applied for the determination of the cumulative urinary excretion of HCQ, DCQ, and DHCQ after oral administration of rac-HCQ to a health volunteer. The results obtained are in agreement with previous literature data.     

Novel derivatives of 3-alkyl-1,5-diaryl-1<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazoles and their pharmacological evaluation as CB<Subscript>1</Subscript> cannabinoid ligands

In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type-1 (CB₁) receptor antagonists. However, the synthesis yields for the ligands were low. Here we present an alternative synthesis pathway with improved yields. In addition, we have synthezised new structural derivatives and studied their results in competitive radioligand binding assays for cannabinoid receptors. Correspondence: Nadine Jagerovic, Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006-Madrid, Spain.     

The synthesis of potential Neramexane metabolites: cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids

A seven step synthetic route toward potential Neramexane metabolites cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids, cis-1 and trans-1, has been developed from isophorone. The synthetic procedure represents a useful method for the preparation of γ-amino acids with both amino and carboxyl groups situated at tertiary carbon atoms.     

1,3,4-Oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives as potential antibacterial agents

Since the introduction of the first antibiotic (penicillin, 1942) into medical practice, to date, there has been an ongoing “race” between scientists creating new drugs and pathogenic bacteria. Antibiotic-bacteria are becoming progressively common, and to make matters worse, more and more bacteria are becoming resistant to all known antibiotics. The traditional method for this problem is to introduce new antibiotics that kill the resistant mutants. This specific “arms race” resulted into thousands of potentially active chemicals are synthesized in laboratories around the world every day.1,3,4-Oxadiazole; 1,3,4-thiadiazole; 1,2,4-triazole and some of their derivatives are involved in modifications at the following axes: First, attaching a thio-group into heterocyclic rings. Second, introducing different substitutions at position 5 which often are the residuals of the synthetic starting materials such as simple aliphatic, substituted aliphatic chains, aromatic carbocyclic and heterocyclic residues.     

Stereoselective determination of hydroxychloro-quine and its major metabolites in human urine by solid-phase microextraction and HPLC

The enantioselective analysis of hydroxychloroquine (HCQ) and its major metabolites was achieved by HPLC and solid-phase microextraction. The chromatographic separation was performed on a Chiralcel OD-H column using hexane/methanol/ethanol (96:2:2, v/v/v) plus 0.2% diethylamine as the mobile phase, at the flow rate of 1.3 mL/min. The main extraction parameters were optimized. The best condition was achieved by the addition of 10% NaCl and 1 mL phosphate buffer 1 mol/L pH 11 to 3 mL human urine. The extraction was conducted for 40 min at 25 degrees C and the desorption time was 3 min using methanol (100%). PDMS-DVB 60 microm fiber was used in this study. The mean recoveries were 9.3, 9.2, and 14.4% for HCQ, desethylhydroxychloroquine (DHCQ), and desethylchloroquine (DCQ), respectively. The method was linear over the range of 50-1000 ng/mL for HCQ enantiomers and over the range of 42-416 ng/mL for DCQ and DHCQ enantiomers. Within-day and between-day precision and accuracy assays for HCQ and its metabolites were lower than 15%. The preliminary 48 h urinary excretion study performed in human urine showed to be stereoselective. The amount of (+)-(S)-enantiomer excreted was higher than its antipode.     

Amino acids as building blocks for the synthesis of substituted 1,2,4-triazoles

We report on the synthesis of 1,2,4-triazoles substituted with 2 or 3 amino acid side chains, using silver benzoate as a key reagent for the cyclization step. A complete study of the optical purity retention during the synthetic process leading to these compounds is described. In addition an improved work-up after the addition-cyclization step was also established leading to better yields and metal-free products.     

1,2,4-Triazole derivative containing thiophen ring: Comparison of theoretical IR and NMR data with experimental

The molecular structure of 1,2,4-triazole containing thiophene derivative which called as ethyl-2-(4-amino-5-oxo-3-(thiophene-2-ylmethyl)-4,5-dihydro-1,2,4-triazole-1-yl) acetate (I) was optimized using DFT/B3LYP method with 6–311++G(d,p) basis set and the structural parameters of the compound were obtained. Thus, the molecular structure was compared with that identified by X-ray analysis. IR and NMR parameters were calculated by DFT/B3LYP/6–311++G(d,p) method. Theoretical vibrational frequencies and NMR chemical shift values were obtained. In addition, the molecular electrostatic potential (MEP) map was calculated. The structural and spectral data obtained from the theoretical study strongly confirm the experimental data. The compatibility of the structural parameters reveal that the choice of the method and the basis function is appropriate.     

新型S(N)-β-D-葡萄糖苷-4-N-(取代邻羟苯基)亚胺基-5-(4-甲基-1,2,3-噻二唑)-1,2,4-三唑的合成及生物活性

在KOH/acetone体系中,4-N-(取代邻羟苯基)亚胺基-5-(4-甲基-1,2,3-噻二唑)-1,2,4-三唑-3-硫酮(3a～3d)与溴-α-D-四乙酰葡萄糖发生Kenigs-Knorr反应,合成了8个未见报道的S(N)-β-D-乙酰葡萄糖苷,其结构经1H NMR、13C NMR、红外光谱及元素分析等确定.目标化合物的生物活性测试结果表明,它们对金黄色葡萄球菌、白色念珠菌和大肠杆菌均显示了较好的抑菌活性,其效果接近或优于对照药物三氯生和氟康唑的抑菌效能.其中,化合物2-N-(2’,3’,4’,6’-O-四乙酰基-β-D-吡喃葡萄糖基)-4-N-(3,5-二溴邻羟苯基)亚胺基-5-(4-甲基-1,2,3-噻二唑)-1,2,4-三唑-3-硫酮(4d)及3-S-(2’,3’,4’,6’-O-四乙酰基-β-D-吡喃葡萄糖硫基)-4-N-(3,5-二溴邻羟苯基)亚胺基-5-(4-甲基-1,2,3-噻二唑)-1,2,4-三唑(5d)具有较强的抑菌活性.