Synthesis and antituberculosis activity of new 3-alkylsulfanyl-1,2,4-triazole derivatives

The increasing clinical importance of drug-resistant mycobacterial pathogens has lent additional urgency to microbiological research and new antimycobacterial compound development. For this purpose, new alkylsulfanyltriazoles were synthesized and evaluated for antituberculosis activity. The reaction of thienyl-2-acetic acid with thiocarbohydrazide gave the mercaptotriazoles (II). The 4-amino-5-(2-thienylmethyl)-3-[1-(2-thienyl)-3-aryl) propion-3-yl] sulfanyl-4H-1,2,4-triazole (III) derivatives were synthesized by reacting the mercaptotriazoles with chalcones (I). Antituberculosis activities of the synthesized compounds were determined by broth microdilution assay, the Microplate Alamar Blue Assay, in BACTEC 12B medium and results were screened in-vitro, using BACTEC 460 Radiometric System against Mycobacterium tuberculosis H37Rv (ATCC 27294) at 6.25 microg/ml and the tested compounds showed considerable inhibition ranging from 58-84%.     

Synthesis of some 4-arylidenamino-4H-1,2,4-triazole-3-thiols and their antituberculosis activity

The increasing clinical importance of drug-resistant mycobacterial pathogens has lent additional urgency to microbiological research and new antimycobacterial compound development. For this purpose, new triazoles were synthesized and evaluated for antituberculosis activity. A series of 4-arylidenamino-4H-1,2,4-triazole-3-thiol derivatives (2a–n) were synthesized from the treatment of 4-amino-4H-1,2,4-triazoles-3-thiol (1) with the respective aldehydes and were evaluated for antituberculosis activity against Mycobacterium tuberculosis H₃₇Rv (ATCC 27294), using the BACTEC 460 radiometric system and BACTEC 12B medium. Compound 2k showed an intereting activity at 6.25 μg/mL with a 87 percentage inhibition.     

Synthesis and preliminary screening of novel N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides as potential atypical antipsychotic agents

A series of N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides were synthesized as prospective novel atypical antipsychotic agents. Microwave irradiation of acetyl glycine (I) with substituted piperazines in the presence of DCC in DMF for about 3-5 min gave the titled compounds (P:1-7). All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D₂ antagonism studies were performed using the climbing mouse assay model and 5-HT_2A antagonism studies were performed using quipazine induced head twitches in mice. Among the synthesized compounds P4 was found to be the most active compound.     

Synthesis and antibacterial properties of new N4-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids

Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and primary α-amino acids (exemplified by glycine, alanine, and l-valine) in aqueous ethanolic NaHCO₃ at 70–80°C for 24–72?h produced the respective N-(4-oxoquinolin-7-yl)-α-amino acids (6a–c). The latter derivatives underwent reductive lactamization upon treatment with Na₂S₂O₄ in aqueous ethanol to afford moderate yields of the corresponding pyrido[2,3-f]quinoxaline-8-carboxylic acids (8a–c). Acetylation of 8a–c using acetyl chloride afforded N₄-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids (9a–c). The structures, assigned to these new heterocyclic products, are supported by analytical and spectral data. The synthesized compounds (6a–c/9a–c) showed appreciable antibacterial activity as compared with ciprofloxacin.     

Synthesis,structure, and antifungal evaluation of some novel 1,2,4-triazolylmercaptoacetylthiosemicarbazide and 1,2,4-triazolylmercaptomethyl-1,3,4-thiadiazole analogs

Novel 1-[[4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-yl]mercaptoacetyl]-4-alkyl/aryl-3-thiosemicarbazides (5–12) were synthesized by the reaction of 4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-ylmercaptoacetylhydrazide (4) with substituted isothiocyanates. Cyclodehydration of thiosemicarbazides with concentrated sulfuric acid yielded 2-[4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-yl]mercaptomethyl-5-alkyl/arylamino-1,3, 4-thiadiazoles (13–17). The new compounds were evaluated for in vitro antifungal activity using the microdilution method. The tested compounds showed varying degrees of activity against Microsporum gypseum NCPF-580, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, and Candida albicans ATCC 10231 (MIC 8–4 μg/mL).     

Amide derivatives with pyrazole carboxylic acids of 5-amino-1,3,4-thiadiazole 2-sulfonamide as new carbonic anhydrase inhibitors: Synthesis and investigation of inhibitory effects

Pyrazole carboxylic acid amides of 5-amino-1,3,4-thiadiazole-2-sulfonamide were synthesized from 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carbonyl chloride and 4-benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl chloride. Carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from human erythrocyte cells by the affinity chromatography method. The inhibitory effects of 5-amino-1,3,4-thiadiazole-2-sulfonamide 1, acetazolamide 2 and new synthesized amides on these isozymes have been studied in vitro. The I₅₀ concentrations (the concentration of inhibitor producing a 50% inhibition of CA activity) against hydratase activity ranged from 1.2 to 2.2 nM for hCA-I and from 0.4 to 2 nM for hCA-II. The I₅₀ values against esterase activity ranged from 1.4 to 8 nM for hCA-I and from 1.3 to 6 nM for hCA-II. The K_i values were observed between 8.2·10^{? 5} to 6.2·10^{? 4} M for hCA-I and between 2.9·10^{? 4} to 8.2·10^{? 4} M for hCA-II. The comparison of new synthesized amides to 5-amino-1,3,4-thiadiazole-2-sulfonamide 1, acetazolamide 2 indicated that the new synthesized compounds (18–23) inhibit CA activity more potently than the parent compounds.     

Synthesis,antioxidant and carbonic anhydrase I and II inhibitory activities of novel sulphonamide-substituted coumarylthiazole derivatives

New secondary benzenesulphonamide-substituted coumarylthiazole derivatives were synthesized and their inhibitory effects on purified carbonic anhydrase I and II were evaluated using CO₂ as a substrate. The result showed that all the synthesized compounds exhibited inhibitory activity on both hCA I and hCA II with N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)naphthalene-2-sulphonamide (5f, IC₅₀ value of 5.63 and 8.48?µM, against hCA I and hCA II, respectively) as the strongest inhibitor revealed from this study. Structure–activity relationship revealed that the inhibitory activity of the synthesized compounds is related to the type of the halogen and bulky substituent on the phenyl ring. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were assayed. 4-methoxy-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)benzenesulphonamide (5e) exhibited the strongest ABTS and CUPRAC activity with IC₅₀ value of 48.83?µM and A_0.50 value of 23.29?µM, respectively.     

Synthesis and antitubercular activity of a series of hydrazone and nitrovinyl analogs derived from heterocyclic aldehydes

A series of hydrazone and 3-nitrovinyl analogs of indole-3-carboxaldehydes and related compounds were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37R_V in BACTEC 12B medium using the Microplate Alamar Blue Assay (MABA). Several compounds showed inhibitory activity against M. tuberculosis in primary screening assays at a concentration of 6.25 μg/mL; subsequent dose-response studies indicated that the most active compounds, 3d, 3e & 8b, had IC₅₀ values of 5.96, 5.4 & 1.6 μg/mL, respectively. These compounds represent potential leads for the further development of novel antitubercular agents.     

Design,synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 2-{4-[4-(2,5-disubstituted thiazol-4-yl)phenylethyl]piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles as atypical antipsychotic agents

A series of 2-{4-[4-(2,5-disubstituted thiazolyl)phenylethyl] piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized either by microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, ¹H NMR, and MS) and the purity was ascertained by microanalysis. The D₂ and 5-HT_2A affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. The D₂ antagonism studies were performed using climbing mouse assay model and 5-HT_2A antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 10f is the most active among the synthesized compounds with 5-HT_2A/D₂ ratio of 1.1286 although the standard drug risperidone exhibited 5-HT_2A/D₂ ratio of 1.0989.     

Inhibitory effect of the compounds from the water extract of Curcuma longa on the production of PGE2 and NO in a macrophage cell line stimulated by LPS

ABSTRACT

We wished to search for the compounds contributing to the anti-inflammatory effects of the water extract of Curcuma longa (WEC). WEC was fractioned and the fractions were evaluated with regard to their inhibitory effect on the production of nitric oxide (NO) from the macrophage cell line stimulated by lipopolysaccharide. Compounds in the active fractions were isolated and identified. One isolated compound was identified as new: (6S)-2-methyl-5-hydroxy-6-(3-hydroxy-4-methylphenyl)-2-heptene-4-one (1). Four isolated compounds were identified as known: (6S)-2-methyl-6-(4-hydroxyphenyl)-2-heptene-4-one (4), bisabolone-4-one (5), curcumenone (6), and turmeronol A (8). Three isolated compounds were not identified their stereostructures but their planar structures: 2-methyl-6-(4-hydroxymethyl-phenyl)-2-heptene-4-one (2), 2-methyl-6-(2,3-epoxy-4-methyl-4-cyclohexene)-2-heptene (3), and 4-methylene-5-hydroxybisabola-2,10-diene-9-one (7). Compounds 1, 4, 7 and 8 inhibited production of prostaglandin E2 and NO. Others inhibited NO production only. These results (at least in part) show the active compounds contributing to the anti-inflammatory effects of WEC, and may be useful for elucidating its various beneficial physiologic effects.     

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by ¹H NMR, ¹³CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1–S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1–S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with K_is in the range of 1.79?±?0.22–2.73?±?0.08?nM against hCA I and in the range of 1.72?±?0.58–11.64?±?5.21?nM against hCA II, respectively.     

Synthesis,anti-inflammatory,analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC₅₀ value 31.59 μg/mL.     

Design,synthesis and evaluation of new thiazole-piperazines as acetylcholinesterase inhibitors

In this study, some new 2-(4-substituted piperazine-1-yl)-N-[4-(2-methylthiazol-4-yl)phenyl]acetamide derivatives were synthesized. The synthesized compounds were screened for their anticholinesterase activity on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes by in vitro Ellman’s method. The structural elucidation of the compounds was performed by using IR, ¹H-NMR, ¹³C-NMR and FAB⁺-MS spectral data and elemental analyses results. Biological assays revealed that at 0.1 µM concentration, the most active compounds against AChE were 5n, 5o and 5p that indicated 96.44, 99.83 and 89.70% inhibition rates, respectively. Besides, IC₅₀ value of the compound 5o was determined as 0.011 µM, whereas IC₅₀ value of standard drug donepezil was 0.054 µM. The synthesized compounds did not show any notable inhibitory activity against BChE.     

Novel 1-(2-pyrimidin-2-yl)piperazine derivatives as selective monoamine oxidase (MAO)-A inhibitors

In the present study, a new series of 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-substituted piperazine-1-carbodithioate derivatives (2a-n) were synthesized and screened for their monoamine oxidase A and B inhibitory activity. The structures of compounds were elucidated using spectroscopic methods and some physicochemical properties of new compounds were predicted using Molinspiration and MolSoft programs. Compounds 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-(4-nitrophenyl)piperazine-1-carbodithioate (2j) and 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-benzhydrylpiperazine-1-carbodithioate (2m) exhibited selective MAO-A inhibitory activity with IC_50?=_?23.10, 24.14?µM, respectively. Some of the biological results were found in accordance with the obtained in silico data based on Lipinski’s fule of five.     

Effects of Trialkyltin Chlorides on Escherichia coli Spheroplasts

Valsa ceratosperma, which is the pathogenic fungus of apple canker, was grown in a synthetic medium. The neutral extract from the culture filtrate was chromatographed on a silica gel column to give five isocoumarins. Their structures were determined by MS, UV, IR, ¹H and ¹³C NMR, and CD spectra. Three of them were known compounds; ( ? )-5-methylmellein (1), ( ? )-5-carboxylmellein (2) and ( ? )-5-hydroxylmethylmellein (3). Since the absolute configurations at C-3 in 2 and 3 were not known until now, both were determined to be R by chemical correlations. The two were new compounds; ( + )-(3R,4S)-trans-4-hydroxy-5-methylmellein (4) and ( ? )-(3R,4R)-cis-4-hydroxy-5-methylmellein (5). All the five compounds showed phytotoxicity in a bioassay using detached apple shoots and lettuce seedlings.     

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC₅₀ = 5.67 μm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC₅₀ = 6.1 μm) and oral (IC₅₀ = 4.17 μm) cancers. These compounds could be of use in designing new anti-cancer agents.     

Improved Targeting of the Flanks of a DNA Stem Using α-Oligodeoxynucleotides.-The Enhanced Effect of an Intercalator

Abstract

2′-Deoxy-5′-0-(4,4′-dimethoxytrityl)-5-methyl-N ⁴-(1-pyrenylmethyl)-α-cytidine (5) was prepared by reaction of 1-pyrenylmethylamine with an appropriate protected 4-(l,2,4-triazolyl)-α-thymidine derivative 3 which was synthesized from 5-O-DMT protected α-thymidine 1. Aminolysis of 3 afforded 3′-O-acetyl-2′-deoxy-5′-O-(4,4′-dimethoxytrityl)-5-methyl-α-cytidine (8). Benzoylation of 8 and removal of acetyl afforded N ⁴-benzoyl-2-deoxy-5–0-(4,4′-dimethoxytrityl)-5-methyl-α-cytidine (10). The amidites of compounds 5and 10 were prepared and used in α-oligonucleotide synthesis. DNA three-way junction (TWJ) is stabilized when an α-ODN is used for targeting the dangling flanks of the stem in a DNA hairpin. Further stabilization of the TWJ is observed when 5 is inserted into the α-ODN at the junction region.

     

毛果鱼藤化学成分及生物活性研究

为了解毛果鱼藤(Derris eriocarpa How)藤茎和根中的生物活性成分,采用柱色谱技术,从其乙酸乙酯萃取部位分离得到6个化合物,分别鉴定为:高丽槐素(1)、美迪紫檀素(2)、大黄素(3)、松脂醇(4)、(6R,9R)9-hydroxy-4-megastigmen-3-one(5)、2-methoxygliricidol(6)。这些化合物均为首次从该植物中分离得到。体外抑菌、细胞毒抑制活性测试结果表明,化合物1、2对部分肿瘤细胞株及结核分枝杆菌(H37Rv)有明显抑制活性。     

Synthesis and bioactivity of 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-oxa(thia)diazol-2-amines

A series of new N′-[N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)thiocarbamoyl]-2-[(1-aryl-1H-tetrazol-5-yl)sulfanyl]acetohydrazides 5a–5e were synthesized rapidly in high yields from 2-(1-aryl-1H-tetrazol-5-ylsulfanyl)acetohydrazides 3a–3e and 2,3,4-tri-O-acetyl-β-d-xylopyranosyl isothiocyanate 4, then 5a–5e were converted to a series of new 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-oxadiazole-2-amines 6a–6e and 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-thiadiazole-2-amines 7a–7e, respectively under mercuric acetate/alcohol system or acetic anhydride/phosphoric acid system, then deacetylated in the solution of CH₃ONa/CH₃OH. All of the novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The structures of compounds 2e, 3e, 5a and 5c have been determined by X-ray diffraction analysis. Some of the synthesized compounds displayed PTP1B inhibition and microorganism inhibition.     

Activity-guided isolation of antileishmanial compounds from Piper hispidum

The bioassay-guided purification of the ethanolic extract from the leaves of Piper hispidum led to the isolation of one new amide, N-2-(3′,4′,5′-trimethoxyphenyl)ethyl-2-hydroxybenzamide (1) as well as two known chalcones 2′-hydroxy-3′,4′,6′-trimethoxychalcone (2); 2′,4′-dihydroxy-6′-methoxychalcone (cardamonin, 3) and one known flavanone, 5,7-dihydroxyflavanone (Pinocembrin, 4). Their structures were elucidated on the basis of spectroscopic data, including homo- and heteronuclear correlation NMR experiments (COSY, HSQC and HMBC) and comparison with data reported in the literature. The isolated compounds were tested against Leishmania amazonensis axenic amastigotes. The results showed that the known chalcone 2 exhibited the most potent antileishmanial activity with an IC₅₀ of 0.8 μM (amphotericin B: IC₅₀ = 0.2 μM) but was shown to exhibit mild cytotoxicity.