The oriented development of antituberculotics: salicylanilides

On the basis of our previous results 22 salicylanilides were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. The Free-Wilson method was used to evaluate structure-antimycobacterial activity relationships. 4-Chloro-N-(4-propylphenyl)salicylamide and 5-chloro-N-(4-propylphenyl)salicylamide were selected for preclinical studies.     

On the relationship between the substitution pattern of thiobenzanilides and their antimycobacterial activity

The goal of this work was to shed more light on a preliminary finding about the relationship between the substitution in the thioacyl part of thiobenzanilides and their antituberculous effect. Thus, we prepared a set of 14 derivatives, out of which eight had not yet been reported, and the compounds were evaluated for antimycobacterial activity on a panel of four Mycobacteria species, including Mycobacterium tuberculosis CNCTC My 331/88, Mycobacterium kansasii CNCTC My 235/80, Mycobacterium avium CNCTC My 330/88 and M. kansasii 6509/96. While the contribution of the substituents with differing electronic and lipophilicity characteristics in position 3 to the antituberculous activity was negligible, we found that unsubstituted position 4 in the thioacyl part appears to be a prerequisite for a thiobenzanilide derivative to possess appreciable biological activity.     

3-Benzyl-2H-1,3-benzoxazine-2,4(3H)-diones, a new group of antimycobacterial compounds against potentially pathogenic strains

A series of derivatives of 3-benzyl-2H-benzoxazine-2,4(3H)-dione substituted in positions 6, 7 or 8 on the benzoxazine, and in positions 3 or 4 on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. The disadvantage of the compounds is in their low solubility in water. The antimycobacterial activity of N-benzylsalicylamides correlates with that of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones and depends on the partition coefficients and electronic indexes.     

小毛茛内酯的合成及抗结核活性的研究(英文)

小毛茛内酯一直被认为是猫爪草抗结核活性的有效成分。本文通过Yamaguchi酯化反应以32.7%的总收率完成了小毛茛内酯的化学合成制备,并采用直观快速药敏实验技术评价了其抗结核活性。文献报道,小毛茛内酯是通过增加外周血淋巴细胞颗粒裂解肽的表达,间接杀死结核杆菌。本文研究结果显示,小毛茛内酯在体外对分支杆菌H37Rv ATCC27294菌株表现出了微弱的抑制活性,其抗结核杆菌作用可能与细胞因子有关。     

含有取代吲哚满二酮-1-乙基的加替沙星衍生物的合成与抗结核作用研究

目的寻找具有优秀活性的喹诺酮类抗结核药物。方法设计合成脂溶性更大的含有取代吲哚满二酮-1-乙基的加替沙星衍生物,测定其体外抗分枝杆菌活性。结果共合成了14个新化合物,其结构经1H-NMR、MS和HRMS确证。目标物普遍具有良好的抗分枝杆菌活性(MIC为1.56~6.25μg/mL),但均弱于其母药加替沙星。其中,化合物3h对草分枝杆菌CMCC93201和耻垢分枝杆菌CMCC93202的活性分别是利福平的4倍和2倍。结论脂溶性并非决定喹诺酮类化合物抗分枝杆菌活性的唯一因素。     

Synthesis and in-vitro antimycobacterial activity of fluoroquinolone derivatives containing a coumarin moiety

A series of gatifloxacin, ciprofloxacin, and 8-OCH(3) ciprofloxacin coumarin derivatives with remarkable improvement in lipophilicity as compared to the parent fluoroquinolones was designed, synthesized, and characterized by (1) H-NMR, MS, and HRMS. These derivatives were evaluated for their in-vitro activity against Mycobacterium smegmatis CMCC 93202 and MTB H37Rv ATCC 27294. All of the synthesized compounds were less active than the parent compounds against M. smegmatis CMCC 93202, but the activity of compound 6 was found to be 2-8-fold more potent than ciprofloxacin, 8-OCH(3) ciprofloxacin, moxifloxacin, and rifampin, and comparable to gatifloxacin against MTB H37Rv ATCC 27294. These results indicated that the lipophilicity of the tested compounds is not the sole parameter affecting antimycobacterial activity.     

Synthesis and antimycobacterial activity of 1,2,4-triazole 3-benzylsulfanyl derivatives

Series of 3-benzylsulfanyl derivatives of 1,2,4-triazole and 4-methyl-1,2,4-triazole were synthesized by alkylation of starting triazole-3-thiol with appropriately substituted benzyl halide. All members of the set were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as the minimum inhibitory concentration. The compounds exhibited only a moderate or slight antimycobacterial activity. Minimum inhibitory concentrations fall into a range of 32->1000 micromol/l. The most active substances bear two nitro groups or a thioamide group on the benzyl moiety. As regards the cytotoxicity effect, the evaluated compounds can be considered as moderately toxic.     

Synthesis, characterization and antimycobacterial activity of Ag(I)-aspartame, Ag(I)-saccharin and Ag(I)-cyclamate complexes

The present work describes the synthesis and antimycobacterial activity of three Ag(I)-complexes with the sweeteners aspartame, saccharin, and cyclamate as ligands, with the aim of finding new candidate substances for fighting tuberculosis and other mycobacterial infections. The minimal inhibitory concentration of these three complexes was investigated in order to determine their in-vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium malmoense, and Mycobacterium kansasii. The MIC values were determined using the Microplate Alamar Blue Assay. The best MIC values found for the complexes were 9.75 microM for Ag(I)-aspartame against M. kansasii and 15.7 microM for Ag(I)-cyclamate against M. tuberculosis.     

Synthesis and antimycobacterial activity of pyridylmethylsulfanyl and naphthylmethylsulfanyl derivatives of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbothioamide/-2-carbonitrile

A set of four types of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbonitrile/-2-carbothioamide substituted with 1-naphthylmethylsulfanyl or pyridylmethylsulfanyl was prepared to modify the structure of benzylsulfanyl derivatives of the above-mentioned heterocycles. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as the minimum inhibitory concentration (MIC). The MIC values fall into a range of 2 to >1000 micromol/L. Introduction of a pyridyl moiety into the molecule mostly decreased the activity. A naphthyl moiety did not influence the activity in comparison with a phenyl. The most active substances were 4-(3-pyridylmethylsulfanyl)pyridine-2-carbothioamide (7b) (MIC = 2 - >62.5 micromol/L) and 4-(1-naphthylmethylsulfanyl)pyridine-2-carbothioamide (7d) (MIC = 2 - >32 micromol/L).     

Facile one-pot synthesis and antimycobacterial evaluation of pyrazolo[3,4-d]pyrimidines

The present article describes a facile one-pot synthesis of a series of eight pyrazolo[3,4-d]pyrimidines 4a-h which were evaluated for their in-vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar-Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in mg/mL. The compounds 4b, 4c, 4d, and 4g exhibited the best results (1.2 microg/mL) when compared with first-line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore, this class of compounds could be a good starting point to develop new lead compounds in the treatment of multidrug-resistant tuberculosis.     

Relationship of chemical structure and anti-inflammatory activity of dihydrocorynantheol and its analogues

BackgroundDihydrocorynantheol (DHC) is an alkaloid compound isolated from Esenbeckia leiocarpa Engl. that has demonstrated anti-inflammatory properties in experimental models. The aim of this study was to investigate whether the modification of the chemical structure of DHC could alter its anti-inflammatory effect in a mouse model of pleurisy induced by carrageenan.MethodsDHC was isolated from Esenbeckia leiocarpa Engl. Capillary electrophoresis, physical characteristics, spectral data produced by infrared analysis and nuclearmagnetic resonance (¹H and ¹³C), andmass spectrometry analysiswere used to identify and elucidate DHC structure. The DHC compound was subjected to chemical structural modifications by nucleophilic substitution reactions, yielding five analogous compounds: acetyl (1), p-methylbenzoyl (2), benzoyl (3), p-methoxybenzoyl (4) and p-chlorobenzoyl (5). Swiss mice were used throughout the experiments. Pro-inflammatory parameters leukocyte migration, exudate concentrations and myeloperoxidase (MPO) activity were quantified in the fluid leakage from the mouse pleural cavities at 4 h after pleurisy induction.ResultsDHC and its analogues acetyl, p-methylbenzoyl, benzoyl, p-methoxybenzoyl and p-chlorobenzoyl inhibited total and differential leukocyte migration andMPOactivity (p < 0.05). OnlyDHCsignificantly decreased the exudate concentrations (p < 0.01).ConclusionsDHC was more effective than its analogues as an anti-inflammatory agent in the mouse model of pleurisy induced by carrageenan.We did not determine what physicochemical modifications altered the anti-inflammatory effect of DHC, but this effect may be due to the modifications on the hydroxyl group at carbon 17 of the DHC.     

3-取代苯甲酰基-4H-色烯-4-酮的合成及其抗快速增殖分枝杆菌活性研究

目的 设计合成3-苯甲酰基-4H-色烯-4-酮类化合物,并测定其体外抗快速增殖分枝杆菌活性。 方法 以焦性没食子酸和取代苯甲酸为原料,经Friedel-Crafts酰基化、Baker-Venkataraman重排等反应合成目标化合物,初步测定了目标化合物的抗快速增殖分枝杆菌活性。结果 共合成8个3-苯甲酰基-4H-色烯-4-酮类化合物,其结构经核磁共振氢谱和质谱确证。化合物2a、2e呈现边缘抗快速增殖分枝杆菌活性。结论 在具有抗快速增殖分枝杆菌活性的天然产物(S)-3-(4-甲氧苄基)-7,8-亚甲二氧基二氢高异黄酮的2,3-位引入双键、7,8-位更换为甲氧基以及9位以羰基替代亚甲基均会导致抗快速增殖分枝杆菌活性的大幅降低。     

Synthesis and biological activity of 5-alkyl-6-(alkylsulfanyl)- or 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides and corresponding thioamides

Nucleophilic substitution of chlorine in 5-alkyl-6-chloropyrazine-2-carboxamides with various alkyl and arylthiolates afforded 20 5-alkyl-6-(alkylsulfanyl)- and 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides. The reaction of the amides with Lawesson's reagent yielded the corresponding thioamides. The assessment of in vitro antimycobacterial and antifungal activity of the compounds was carried out. In both series, the antimycobacterial activity increases with increasing molecular weight of the alkylsulfanyl group in position 6 of the pyrazine ring. Thioamides exhibited higher activity than the corresponding amides. 5-Butyl-6-(phenylsulfanyl)pyrazine-2-carbothioamide (2j) possessed the highest activity (91% inhibition) against Mycobacterium tuberculosis and also the highest lipophilicity (log P = 4.95). Only a poor in vitro antifungal effect was noted in 5-butyl-6-(butylsulfanyl)pyrazine-2-carboxamide (1i) and 6-(ethylsulfanyl)-5-isobutylpyrazine-2-carbothioamide (2q) against Trichophyton mentagrophytes and Absidia corymbifera.     

Ring substituted 3-phenyl-1-(2-pyrazinyl)-2-propen-1-ones as potential photosynthesis-inhibiting, antifungal and antimycobacterial agents

Four series of ring substituted (E)-3-phenyl-1-(2-pyrazinyl)-2-propen-1-ones were prepared by means of modified Claisen-Schmidt condensation of acetylpyrazines with aromatic aldehydes. The structures were confirmed by elemental analysis, IR, 1H NMR and 13C NMR spectra. The compounds were tested for specific biological properties and some derivatives exhibited photosynthesis-inhibiting, antifungal and antimycobacterial properties. The most pronounced effects were observed with compounds substituted with phenolic groups. Ortho-hydroxyl substituted derivatives were more potent than the corresponding para-hydroxyl substituted analogues.     

Type II pneumocytes in the evaluation of drug antimycobacterial activity

In order to combat the worldwide increase in the prevalence of multi-drug resistant tuberculosis and Mycobacterium avium complex infections, a number of new antimycobacterial drugs has been synthesised and developed. There is great promise for drugs designed by new strategies, especially those based on the information on mycobacterial genome sequences and a host-parasite relationship. Moreover, the development of new protocols for chemotherapy of intractable mycobacterioses is also needed. For this purpose, better in vitro drug activity assay models that enable prediction of therapeutic activity, particularly those predicting the in vivo sterilising activity, are urgently needed, since the ordinary in vitro methods are inefficient indicators of clinical efficacy. In this context, the in vitro models using Type II pneumocytes, which play an important role in the establishment of mycobacterial pulmonary infections as a portal of mycobacterial organisms to the lungs, are considerably useful, especially in predicting the in vivo activity of certain drugs against Mycobacterium avium complex infection.     

Synthesis and in vitro antimycobacterial activity of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-4,5-dihydro-1H-1-(isonicotinoyl) pyrazoles

A series of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-1H-1-isonicotinoyl-4,5-dihydropyrazoles (2a-i) were synthesised by the cyclocondensation reaction of 4-methoxy-1,1,1-trifluoro[chloro]-4-(substituted)-alk-3-en-2-ones (1a-i) and isoniazid (INH). Their in vitro antimicrobial activity was tested against INH-susceptible Mycobacterium tuberculosis H37Rv, INH-resistant clinical M. tuberculosis isolates and non-tuberculous mycobacteria. Amongst the synthesised compounds, 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)-pyrazole (2a) and 5-hydroxy-3-(4-methylphenyl)-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl) pyrazole (2d) were found to be the two most active agents against susceptible M. tuberculosis and several INH-resistant strains. The compound 3-(2-furyl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)pyrazole (2f) was active against all the INH-resistant strains regardless of the genetic background at concentrations two- to four-fold its minimum inhibitory concentration against M. tuberculosis H37Rv. These compounds were inhibitors of mycolic acid biosynthesis, in agreement with the utilisation of the INH scaffold for their design. Interestingly, the most active compound against M. tuberculosis, 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)-pyrazole (2a), was even more potent than INH against non-tuberculous mycobacteria.     

Synthesis, structure and biological activity of novel 1,2,4-triazole mannich bases containing a substituted benzylpiperazine moiety

A series of novel Mannich bases with trifluoromethyl-1,2,4-triazole and substituted benzylpiperazine moieties were synthesized. Their structures were confirmed by IR, (1) H NMR and elemental analysis. The single crystal structure of compound 4r was also determined. The preliminary bioassays showed that most of the lead compounds had low herbicidal activity against Brassica campestris, Echinochloa crusgalli, and KARI enzyme. However, most of them exhibited significant fungicidal activity at the dosage of 50 μg/mL toward five test fungi. Among the 18 novel compounds, several showed superiority over the commercial fungicide Triadimefon against Cercospora arachidicola and Fusarium oxysporum f. sp. cucumerinum during this study. Meanwhile, some compounds displayed plant growth regulatory activity at the dosage of 10 μg/mL.     

Stimulus properties of benzodiazepines: correlations with binding affinities,therapeutic potency,and structure activity relationships (SAR)

Using a two-lever operant choice task, rats were trained to discriminate diazepam (3.0 mg/kg) from saline under a fixed-ratio 10 (FR10) schedule of reinforcement. Once the discrimination was learned, generalization studies were conducted using various doses of 17 benzodiazepine derivatives. The diazepam stimulus generalized in a dose-related manner to each of these compounds. ED₅₀ values were compared with available data on displacing affinities (K _i values) for tritiated diazepam brain binding in man, and with human therapeutic potency. A significant correlation (r=0.88, n=9) was found between benzodiazepine binding affinities and ED50 values derived from the diazepam stimulus generalization assay. A significant correlation (r=0.92, n=10) was also found between drug discrimination ED₅₀ values and human therapeutic potencies. Finally, the benzodiazepine structure activity relationships generated from the drug discrimination studies closely paralleled the known structure activity relationships for these agents. The results provide further evidence that benzodiazepines exert their pharmacological effects through an interaction with benzodiazepine receptors.