Substituted pyrazinecarboxamides: synthesis and biological evaluation

Condensation of the corresponding chlorides of some substituted pyrazine-2-carboxylic acids (pyrazine-2-carboxylic acid, 6-chloropyrazine-2-carboxylic acid, 5-tert-butylpyrazine-2-carboxylic acid or 5-tert-butyl-6-chloropyrazine-2-carboxylic acid) with various ring-substituted aminothiazoles or anilines yielded a series of amides. The syntheses, analytical and spectroscopic data of thirty newly prepared compounds are presented. Structure-activity relationships between the chemical structures and the anti-mycobacterial, antifungal and photosynthesis-inhibiting activity of the evaluated compounds are discussed. 3,5-Bromo-4-hydroxyphenyl derivatives of substituted pyrazinecarboxylic acid, 16-18, have shown the highest activity against Mycobacterium tuberculosis H(37)Rv (54-72% inhibition). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 5-tert-butyl-6-chloro-N-(4-methyl-1,3-thiazol-2-yl)pyrazine-2-carboxamide (8, MIC =31.25 micromol x mL(-1)). The most active inhibitors of oxygen evolution rate in spinach Molecules 2006, 11,243 chloroplasts were the compounds 5-tert-butyl-6-chloro-N-(5-bromo-2-hydroxyphenyl)- pyrazine-2-carboxamide (27, IC(50) = 41.9 micromol x L(-1)) and 5-tert-butyl-6-chloro-N-(1,3- thiazol-2-yl)-pyrazine-2-carboxamide (4, IC50 = 49.5 micromol x L(-1)).     

Substituted N-phenylpyrazine-2-carboxamides, their synthesis and evaluation as herbicides and abiotic elicitors

The condensation of substituted pyrazine-2-carboxylic acid chlorides with ring-substituted anilines yielded five substituted pyrazine-2-carboxylic acid amides. Thesynthesis, and analytical, lipophilicity and biological data of the newly synthesizedcompounds are presented in this paper. The photosynthesis inhibition, antialgal activityand the effect of a series of pyrazine derivatives as abiotic elicitors on the accumulation offlavonoids in a callus culture of Ononis arvensis (L.) were investigated. The most activeinhibitor of the oxygen evolution rate in spinach chloroplasts was 6-chloro-pyrazine-2-carboxylic acid (3-iodo-4-methylphenyl)-amide (2, IC(50) = 51.0 micromol.L(-1)). The highestreduction of chlorophyll content in Chlorella vulgaris was found for 5-tert-butyl-N-(4-chloro-3-methylphenyl)-pyrazine-2-carboxamide (3, IC(50) = 44.0 micromol.L(-1)). The maximalflavonoid production (about 900%) was reached after a twelve-hour elicitation processwith 6-chloropyrazine-2-carboxylic acid (3-iodo-4-methylphenyl)-amide (2).     

Investigating the spectrum of biological activity of substituted quinoline-2-carboxamides and their isosteres

In this study, a series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted naphthalene-2-carboxamides were prepared and characterized. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial species. N-Cycloheptylquinoline-2-carboxamide, N-cyclohexylquinoline-2-carboxamide and N-(2-phenylethyl)quinoline-2-carboxamide showed higher activity against M. tuberculosis than the standards isoniazid or pyrazinamide and 2-(pyrrolidin-1-ylcarbonyl)quinoline and 1-(2-naphthoyl)pyrrolidine expressed higher activity against M. kansasii and M. avium paratuberculosis than the standards isoniazid or pyrazinamide. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC(50) value of the most active compound N-benzyl-2-naphthamide was 7.5 μmol/L. For all compounds, the structure-activity relationships are discussed.     

Design,synthesis and anti-mycobacterial evaluation of some new <Emphasis Type="Italic">N</Emphasis>-phenylpyrazine-2-carboxamides

N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various positions) were previously shown to possess significant biological activities in vitro, markedly anti-mycobacterial and photosynthesis-inhibiting activity. Based on structure-activity relationships (SAR) extracted from previously published series, 25 new anilides of non-substituted pyrazinoic acid (POA), 5-CH₃-POA, 6-Cl-POA, 5-tert-butyl-POA and 5-tert-butyl-6-Cl-POA were designed and synthesised. The phenyl part was substituted with simple hydrophobic substituents chosen from methyl and halogens. 5-tert-Butyl-N-(5-fluoro-2-methylphenyl)pyrazine-2-carboxamide (9), N-(3-chloro-4-methylphenyl)-5-methylpyrazine-2-carboxamide (12), 6-chloro-N-(3-chloro-4-methylphenyl)pyrazine-2-carboxamide (13) and 6-chloro-N-(5-iodo-2-methylphenyl)pyrazine-2-carboxamide (18) possessed whole cell anti-mycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) of around 10 μM. Importantly, no cytotoxicity in the HepG2 model was detected in vitro at the concentrations tested and the estimated IC50 values were in hundreds of μM, indicating promising selectivity. N-(3-Chloro-4-methylphenyl)pyrazine-2-carboxamide (11) and N-(4-chloro-2-iodophenyl)pyrazine-2-carboxamide (21) exerted significant activity against Mycobacterium kansasii with MIC 12.6 μM and 8.7 μM, respectively. No activity was detected against Mycobacterium avium. SAR were in accordance with those observed for the derivatives previously published.     

Synthesis and characterization of (Z)-5-arylmethylidene-rhodanines with photosynthesis-inhibiting properties

A series of rhodanine derivatives was prepared. The synthetic approach, analytical and spectroscopic data of all synthesized compounds are presented. Lipophilicity of all the discussed rhodanine derivatives was analyzed using the RP-HPLC method. The compounds were tested for their ability to inhibit photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts and reduce chlorophyll content in freshwater alga Chlorella vulgaris. Structure-activity relationships between the chemical structure, physical properties and biological activities of the evaluated compounds are discussed. For majority of the tested compounds the lipophilicity of the compound and not electronic properties of the R1 substituent were decisive for PET-inhibiting activity. The most potent PET inhibitor was (5Z)-5-(4-bromobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (IC(50) = 3.0 μmol/L) and the highest antialgal activity was exhibited by (5Z)-5-(4-chlorobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (IC(50) = 1.3 μmol/L).     

Antifungal Activity of Salicylanilides and Their Esters with 4-(Trifluoromethyl)benzoic Acid

Searching for novel antimicrobial agents still represents a current topic in medicinal chemistry. In this study, the synthesis and analytical data of eighteen salicylanilide esters with 4-(trifluoromethyl)benzoic acid are presented. They were assayed in vitro as potential antimycotic agents against eight fungal strains, along with their parent salicylanilides. The antifungal activity of the presented derivatives was not uniform and moulds showed a higher susceptibility with minimum inhibitory concentrations (MIC) 3 0.49 μmol/L than yeasts (MIC 3 1.95 μmol/L). However, it was not possible to evaluate a range of 4-(trifluoromethyl)benzoates due to their low solubility. In general, the most active salicylanilide was N-(4-bromophenyl)-4-chloro-2-hydroxybenzamide and among esters, the corresponding 2-(4-bromophenylcarbamoyl)-5-chlorophenyl 4-(trifluoromethyl) benzoate exhibited the lowest MIC of 0.49 μmol/L. However, the esterification of salicylanilides by 4-(trifluoromethyl)benzoic acid did not result unequivocally in a higher antifungal potency.     

Investigating spectrum of biological activity of 4- and 5-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides

In this study, a series of twenty-two 5-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides and ten 4-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides is described. The compounds were analyzed using RP-HPLC to determine lipophilicity. Primary in vitro screening of the synthesized compounds was performed against mycobacterial, bacterial and fungal strains. They were also evaluated for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The compounds showed biological activity comparable with or higher than the standards isoniazid, fluconazole, penicillin G or ciprofloxacin. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure-activity relationships are discussed.     

Synthesis,antimicrobial, antiquorum-sensing and cytotoxic activities of new series of benzothiazole derivatives

New series of benzothiazole derivatives were designed and synthesized. The newly synthesized compounds were screened for their antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus cereus. Compounds 6j and 6o showed the highest activity against E. coli and S. aureus. The antifungal activity of these compounds was also tested against Candida albicans and Aspergillus fumigatus293. Compounds 4c, 4g and 6j exhibited the highest activity against C. albicans. In addition, compounds4 a and 6j displayed promising activity against A. fumigatus 293. The same compounds were examined for their antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, whereas compounds4 a, 6j and 6p showed moderate activity. The in vitro cytotoxicity testing of the synthesized compounds was performed against cervical cancer(Hela) and kidney fibroblast cancer(COS-7) cell lines. Results indicated that all tested compounds have IC50 values 50 mmol/L against both cell lines. Molecular properties, toxicities, drug-likeness, and drug score profiles of compounds 4a–c, 5a, 6g,h, 6j, 6l, 6o and7 c,d were also assessed.     

Antimycobacterial activity of salicylanilide benzenesulfonates

A series of eighteen novel esters of salicylanilides with benzenesulfonic acid were designed, synthesized and characterized by IR, 1H-NMR and 13C-NMR. They were evaluated in vitro as potential antimycobacterial agents towards Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. In general, the minimum inhibitory concentrations range from 1 to 500 μmol/L. The most active compound against M. tuberculosis was 4-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)-phenyl benzenesulfonate, with MIC of 1 μmol/L and towards M. kansasii its isomer 5-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl benzenesulfonate (MIC of 2-4 μmol/L). M. avium was the less susceptible strain. However, generally, salicylanilide benzenesulfonates did not surpass the activity of other salicylanilide esters with carboxylic acids.     

Determination of the anxiolytic agent 8-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,5-alpha] [1,4]-benzodiazepine-3-carboxamide in whole blood, plasma or urine by high-performance liquid chromatography

A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the determination of 8-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,5-alpha]-[1,4]-benzodiazepine-3-carboxamide [I] and its 4-hydroxy metabolite, 8-chloro-6-(2-chlorophenyl)-4-hydroxy-4H-imidazo-[1,5-alpha] [1,4]-benzodiazepine-3-carboxamide [II] in whole blood, plasma or urine. The assay for both compounds involves extraction into diethyl ether-methylene chloride (70:30) from blood, plasma, or urine buffered to pH 9.0. The overall recoveries of [I] and [II] are 92.0 +/- 5.4% (S.D.) and 90.3 +/- 4.9% (S.D.), respectively. The sensitivity limit of detection is 50 ng/ml of blood, plasma, or urine using a UV detector at 254 nm. The HPLC assay was used to monitor the blood concentration-time fall-off profiles, and urinary excretion profiles in the dog following single 1 mg/kg intravenous and 5 mg/kg oral doses, and following multiple oral doses of 100 mg/kg/day of compound [I].     

Synthesis and pesticidal activities of novel anthranilic diamides containing pyridylpyrazole and iminodithiocarbamate or thiosemicarbazone motifs

Abstract

A series of novel anthranilic diamide derivatives containing pyridylpyrazole and iminodithiocarbamate or thiosemicarbazone motifs were synthesized via multi-step reactions. The structures of seven title compounds (methyl 2-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3- methylbenzylidene)hydrazinecarbodithioate 7 and 3-bromo-N-(2-((2-substitutedcarbamothioylhydrazono)methyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide 8a-8f) were confirmed by melting points, IR, ¹H NMR, ¹³C NMR, and HRMS. The bioassays showed that some of the compounds exhibited modest insecticidal activities against oriental armyworm (Mythimna separata Walker), particularly, compound 8b (3-bromo-N-(4-chloro-2-methyl-6-((2-(methylcarbamothioyl)hydrazono)methyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide) held 100% and 30% larvicidal activity at the concentration of 25?mg/L and 10?mg/L, respectively. In addition, several compounds displayed favorable fungicidal activities against Alternaria solani Sorauer and Physalospora piricola at 50?μg/mL, and were comparable with the controls Chlorothalonil and Triadimefon. The results in this paper will provide important information for further research and development of sulfur-containing heterocyclic agrochemicals.     

Synthesis and biological activity of novel N-(3-furan-2-yl-1-phenyl-1H-pyrazol-5-yl) amides derivatives

A series of novel N-(3-furan-2-yl-1-phenyl-1H-pyrazol-5-yl) amides derivatives were designed and synthesized. Their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS. All title compounds were evaluated for their herbicidal and antifungal activities. Preliminary bioassay results indicated that the title compounds showed good to moderate herbicidal activity at 1000 mg/L. Compound 6q presented the best activity against Digitaria sanguinalis (L) Scop., Amaranthus retroflexus L. and Arabidopsis thaliana with an inhibition degree of five. Compound 6d also showed an inhibition degree of five against D. sanguinalis. In addition, at 50 mg/L, most compounds exhibited good in vitro antifungal activity against Sclerotinia sclerotiorum, with compound 6c showing over 90% antifungal activity against S. sclerotiorum and Pellicularia sasakii.     

Synthesis and antifungal activity of novel 1,2,4-triazole derivatives containing an amide moiety

A series of novel 1,2,4-triazol derivatives containing an amide moiety were synthesized and their antifungal activities were evaluated. The results indicated that some of the target compounds possessed good antifungal activities. Among them, compounds 6a , 6g , 6k , and 6m showed excellent antifungal activities against Botrytis cinerea, with an inhibition rate of 91.8%, 90.1%, 93.6%, and 91.2% at a concentration of 50 μg/mL, which were superior to that of Pyrimethanil (82.8%). Meanwhile, compound 6b showed better antifungal activity against Phompsis sp, with an inhibition rate of 92.4%, in comparison with that of Pyrimethanil (85.1%).     

Design,synthesis, and antifungal evaluation of novel coumarin-pyrrole hybrids

A series of coumarin derivatives bearing a pyrrole scaffold were designed, prepared, and assessed for their in vitro antifungal activities against six phytopathogenic fungi. The antifungal activity screening results suggest that some synthesized hybrids exhibited potential fungicidal activities against the tested fungi. In particular, compounds 6j , 6k , 6o , 6p , and 6r displayed significant antifungal effects against Rhizoctorzia solani, and possessed EC₅₀ values of 3.94, 7.75, 6.38, 6.25, and 7.67 μg/ mL, respectively. The above activities are more potent than the commercialized fungicide Boscalid (11.52 μg/mL) and Osthole (9.79 μg/mL). These results provide a significant reference for further rational design of coumarin-based fungicides.     

2-位或4-位取代吡啶并嘧啶类非经典叶酸拮抗剂的合成及抗肿瘤活性

以非经典叶酸拮抗剂2,4-二氨基-6-(4-甲基苯基)乙基吡啶并[3,2-d]嘧啶(wm-5b)及其侧链简化产物2,4-二氨基吡啶并[3,2-d]嘧啶为先导化合物, 选取具有抗肿瘤活性的基团, 通过微波法高效合成了2-位或4-位取代吡啶并嘧啶类非经典叶酸拮抗剂, 研究了2-位及4-位取代基对抗肿瘤活性的影响, 为非经典叶酸拮抗剂的设计合成提供了更多的理论依据. 目标化合物的结构均经核磁共振波谱(NMR)和质谱(MS)确证. 生物活性测定结果表明, 所有目标化合物均具有抗肿瘤活性, 其中, 6-(4-甲基苯基)乙基-4-氨基-2-(3-氯-4-氟苯基)氨基吡啶并[3,2-d]嘧啶(6b)对HL-60细胞的IC₅₀=(4.09±0.48) μmol/L, 对A549细胞的IC₅₀=(17.99±7.20) μmol/L, 而对HCT116细胞的IC₅₀=(14.52±4.74) μmol/L; 部分目标化合物具有二氢叶酸还原酶抑制活性. 此外, 对部分目标化合物和先导物进行了二氢叶酸还原酶晶体结构的分子对接, 对活性结果和构效关系从分子水平上进行解释.     

Isomannide monoundecenoate-based 1,2,3-triazoles: Design,synthesis, and in vitro bioactive evaluation

A new series of isomannide monoundecenoate-based 1,2,3-triazole analogs 6a–e were designed by employing click chemistry in good yields. in vitro bioactive assay manifested that the several target compounds exhibited promising antibacterial and antifungal activities. Notably, compounds having phenyl substituted triazole 6a , and hydroxy phenyl substituted triazole 6b possessed highly selective promising inhibition towards Gram-positive bacterial strains namely Bacillus subtilis and Staphylococcus aureus with MIC value of 3.9 μg/mL. Further, these potential hybrids ( 6a and 6b) also exhibited highly impressive antifungal activity against the tested panel of Candida strains with MIC value of 3.9 μg/mL. Based on our in vitro preliminary antimicrobial study, these two compounds 6a and 6b have been identified as potential antimicrobial lead compounds. Moreover, all prepared derivatives were also evaluated for their in vitro cytotoxic activities against A549, MCF7, DU145 and HeLa cancer cell lines. The results indicated that only the hydroxy phenyl substituted triazole analog 6b displayed good cytotoxic activity towards all tested human cancer cell lines without any significant effects on normal cell line (HUVEC).     

Thiourea Derivatives,Simple in Structure but Efficient Enzyme Inhibitors and Mercury Sensors

In this study six unsymmetrical thiourea derivatives, 1-isobutyl-3-cyclohexylthiourea (1), 1-tert-butyl-3-cyclohexylthiourea (2), 1-(3-chlorophenyl)-3-cyclohexylthiourea (3), 1-(1,1-dibutyl)-3-phenylthiourea (4), 1-(2-chlorophenyl)-3-phenylthiourea (5) and 1-(4-chlorophenyl)-3-phenylthiourea (6) were obtained in the laboratory under aerobic conditions. Compounds 3 and 4 are crystalline and their structure was determined for their single crystal. Compounds 3 is monoclinic system with space group P2₁/n while compound 4 is trigonal, space group R³:H. Compounds (1–6) were tested for their anti-cholinesterase activity against acetylcholinesterase and butyrylcholinesterase (hereafter abbreviated as, AChE and BChE, respectively). Potentials (all compounds) as sensing probes for determination of deadly toxic metal (mercury) using spectrofluorimetric technique were also investigated. Compound 3 exhibited better enzyme inhibition IC₅₀ values of 50, and 60 µg/mL against AChE and BChE with docking score of −10.01, and −8.04 kJ/mol, respectively. The compound also showed moderate sensitivity during fluorescence studies.     

Investigating the spectrum of biological activity of ring-substituted salicylanilides and carbamoylphenylcarbamates

In this study, a series of twelve ring-substituted salicylanilides and carbamoylphenylcarbamates were prepared and characterized. The compounds were analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Moreover, their site of action in the photosynthetic apparatus was determined. Primary in vitro screening of the synthesized compounds was also performed against mycobacterial, bacterial and fungal strains. Several compounds showed biological activity comparable with or higher than the standards 3-(3,4-dichlorophenyl)-1,1-dimethylurea, isoniazid, penicillin G, ciprofloxacin or fluconazole. The most active compounds showed minimal anti-proliferative activity against human cells in culture, indicating they would have low cytotoxicity. For all compounds, the relationships between lipophilicity and the chemical structure are discussed.     

含6-氟喹唑啉片段的新型1,3,4-噁(噻)二唑类衍生物的合成及抗菌活性研究

为寻找高效农用抗菌先导化合物,通过活性亚结构拼接法设计合成了50个含6-氟喹唑啉片段的新型1,3,4-噁(噻)二唑类衍生物6 a?6 y和8a?8y,其结构经¹H NMR、¹³C NMR和HRMS手段进行了表征,且化合物6i和8x的结构最终由X射线单晶衍射法加以确认.初步抗菌测试表明,部分化合物表现出较好的体外抗真菌活性.在50μg/m L浓度下,化合物6b、6d、6t、6v和6x对小麦赤霉病菌的抑制率分别为58%、58%、55%、63%和60%,化合物6 v和8v对苹果腐烂病菌的抑制率分别为71%和64%,化合物6 v对油菜炭疽病菌的抑制率为72%,它们均优于对照药剂噁霉灵(分别为51%、61%和70%).此外,部分化合物在100μg/m L浓度下也表现出一定的体外抗细菌活性.