Synthesis and Antimicrobial Evaluation of 6‐Alkylamino‐N‐phenylpyrazine‐2‐carboxamides

This work presents synthesis and antimicrobial evaluation of nineteen 6‐alkylamino‐N–phenylpyrazine‐2‐carboxamides. Antimycobacterial activity was determined against Mycobacterium tuberculosis H37Rv, M. kansasii and two strains of M. avium. Generally, the antimycobacterial activity increased with prolongation of simple alkyl chain and culminated in compounds with heptylamino substitution ( 3e , 4e ) with MIC = 5–10 μm against M. tuberculosis H37Rv. On the contrary, derivatives with modified alkyl chain (containing e.g. terminal methoxy or hydroxy group) as well as phenylalkylamino derivatives were mainly inactive. The most active compounds (with hexyl to octylamino substitution) were evaluated for their in vitro activity against drug‐resistant strains of M. tuberculosis and possessed activity comparable to that of the reference drug isoniazid. None of the tested compounds were active against M. avium. Some derivatives exhibited activity against Gram‐positive bacteria including methicillin‐resistant Staphylococcus aureus (best MIC = 7.8 μm ), while Gram‐negative strains as well as tested fungal strains were completely unsusceptible. Active compounds were tested for in vitro toxicity on various cell lines and in most cases were non‐toxic up to 100 μm .     

Antimycobacterial properties of antihistaminic compounds

Antimycobacterial Properties of Antihistaminic Compounds The testing for antimycobacterial properties (M. tuberculosis H 37 Ra, Middlebrook-7H9-broth) of the antihistaminic compounds 1–15 is described. These compounds are specific growth inhibitors of Mycobacterium tuberculosis H 37 Ra.     

Synthesis,biological evaluation,and molecular docking studies of novel 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles derivatives targeting Mycobacterium tuberculosis

A small library of new 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles was synthesized and screened for the antimycobacterial potency against Mycobacterium tuberculosis H₃₇Ra strain and Mycobacterium bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti‐TB activity in the range of IC₅₀0.03–5.88 μg/ml for dormant stage and 20 compounds in the range of 0.03–6.96 μg/ml for active stage. Their lower toxicity (>100 μg/ml) and higher selectivity (SI = >10) against all cancer cell lines screened make them interesting compounds with potential antimycobacterial effects. Furthermore, to rationalize the observed biological activity data and to establish a structural basis for inhibition of M. tuberculosis, the molecular docking study was carried out against a potential target MTB CYP121 which revealed a significant correlation between the binding score and biological activity for these compounds. Cytotoxicity and in vivo pharmacokinetic studies suggested that 1,2,4‐triazole analogues have an acceptable safety index, in vivo stability and bio‐availability.     

Antimycobakteriell wirksame Carbazolderivate

Carbazol Derivatives with Antimycobacterial Activity Carbazoles are synthesized and tested for antimycobacterial properties (M. tuberculosis H 37 Ra, Middlebrook-7H9-broth). - The different antimycobacterial properties of diastereomeres are examined using compounds 32 and 33 , those of a racemic compound and the (+)-enantiomer are tested with (±)- 12 /(+)- 12 and (±)- 5 /(+)- 5 , respectively. - (+)- 12 is prepared by enantioselective synthesis.     

Antimycobacterial activity of fusaric acid from a mangrove endophyte and its metal complexes

Due to the increasing prevalence of multidrug-resistant Mycobacterium tuberculosis, there is an urgent need for new antituberculosis drugs that have novel mechanisms of action. As part of our ongoing search for antimycobacterial metabolites from mangrove endophytes, chemical analysis of the active extract of a strain of Fusarium sp. was performed, which led to the isolation of fusaric acid as the predominant constituent. A variety of metal complexes of fusaric acid were prepared. Antimycobacterial assays showed that Cadmium (II) and Copper (II) complexes exhibited potent inhibitory activity against the M. bovis BCG strain [minimum inhibitory concentration (MIC) = 4 μg/mL] and the M. tuberculosis H37Rv strain (MIC = 10 μg/mL), respectively. This is the first report of the antimycobacterial activity of the mangrove Fusarium metabolite and its coordinating metal complexes.     

Synthesis and antituberculous activity of quinoline isosteres of isoniazid

We present an evaluation of the antimycobacterial activity of a series of 2-aryl(heteryl)-4-quinolinecarboxylic acids. Compounds with potential value against Mycobacterium tuberculosis H37Rv were found.     

Preparation and in‐vitro Evaluation of 4‐Benzylsulfanylpyridine‐2‐carbohydrazides as Potential Antituberculosis Agents

A set of 4‐benzylsulfanylpyridine‐2‐carbohydrazides was synthesized and evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, non‐tuberculous mycobacteria, and multidrug‐resistant M. tuberculosis. The activities expressed as the minimum inhibitory concentration (MIC) fall into a range of 2 to 125 μmol/L, most often 4 to 32 μmol/L. The results revealed that the substituents on the benzyl moiety do not influence the antimycobacterial efficacy. The substances exhibited similar activities against sensitive and resistant strains of M. tuberculosis. Furthermore, compounds show low antiproliferative effect and cytotoxicity.     

Lauric acid and myristic acid from Allium sativum inhibit the growth of Mycobacterium tuberculosis H37Ra: in silico analysis reveals possible binding to protein kinase B

Context: The bulb of Allium sativum Linn (Alliaceae) has numerous medicinal values. Though the petroleum ether extract of the bulb has shown to exhibit antimycobacterial activity, the phytochemical(s) responsible for this inhibitory activity is not known.

Objective: To characterize the bioactive compounds in the petroleum ether extract of Allium sativum (garlic) that inhibit the growth of Mycobacterium tuberculosis H37Ra.

Materials and methods: Bioactivity-guided fractionation was employed to isolate the bioactive compounds. Antimycobacterial activity was evaluated by well-diffusion method and microplate alamar blue assay (MABA). Infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy were used to characterize the bioactive compounds. Autodock was used to obtain information on molecular recognition, and molecular dynamics simulation was performed using GROMACS.

Results: The bioactive compounds that inhibited the growth of M. tuberculosis H37Ra were found to be lauric acid (LA) and myristic acid (MA). The minimal inhibitory concentration of LA and MA was found to be 22.2 and 66.7?μg/mL, respectively. In silico analysis revealed that these fatty acids could bind at the cleft between the N-terminal and C-terminal lobes of the cytosolic domain of serine/threonine protein kinase B (PknB).

Discussion and conclusion: The inhibition activity was dependent on the alkyl chain length of the fatty acid, and the amino acid residues involved in binding to fatty acid was found to be conserved across the Pkn family of proteins. The study indicates the possibility of using fatty acid derivatives, involving Pkn family of proteins, to inhibit the signal transduction processes in M. tuberculosis.     

Synthesis and antimycobacterial activity of novel 4-[5-(substituted phenyl)-1-phenyl-4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-3-pyrazolyl]-2-methylphenol derivatives

In the present investigation, 4-hydroxy-3-methylacetophenone, on condensation with appropriate aldehydes in methanolic potassium hydroxide solution, yielded the corresponding chalcones (C_I-XI). These corresponding chalcones were reacted with phenyl hydrazide in glacial acetic acid, which led to the formation of novel 4-[5-(substituted phenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-2-methylphenol derivatives. All newly synthesized compounds were evaluated for their antimycobacterial activities against isoniazid-resistant Mycobacterium tuberculosis using agar dilution. 4-[5-(4-Fluoro phenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-2-methylphenol showed good antimycobacterial activity, with a minimum inhibitory concentration of 0.62 μg/ml.     

Synthesis and antimycobacterial activity of substituted 2-nitro-1-(4-tolylsulfonyl)-2-(3-methylphenyl-1,2,4-oxadiazol-5-yl)ethanes

A series of substituted 2-nitro-1-(4-tolylsulfonyl)-2-(3-methylphenyl-1,2,4-oxadiazol-5-yl)ethanes were synthesized and their antimycobacterial activity with respect to Mycobacterium Lufu and Mycobacterium tuberculosis species was studied. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 7, pp. 30–31, July, 2006.     

Synthesis and evaluation of isonicotinoyl hydrazone derivatives as antimycobacterial and anticancer agents

A new series of isonicotinoyl hydrazone derivatives (3a–3o) have been synthesized, characterized and evaluated for in vitro antimycobacterial activity against M. tuberculosis H37Rv and two clinical isolates using tetrazolium microplate assay (TEMA). Some of these compounds showed moderate to good antimycobacterial activity at micro molar concentrations. Among them, 3k and 3m were the most potent analogues with an inhibition concentration at 0.59 and 0.65 μM, respectively, against M. tuberculosis H37Rv compared to parent drug, isoniazid (0.57 μM). Additionally, all the synthesized compounds were subjected to in vitro anticancer activity against human colorectal cancer cell lines (HCT 116). Compounds 3b and 3l displayed antiproliferative activity at inhibitory concentration 3.1 and 0.29 μM, respectively, when compared to standard, 5-fluorouracil (5 μM). These results can be considered as an important start point for the rational design of new leads for antitubercular and anticancer drug discovery.     

2‐Aryl‐3‐(1H‐Azol‐1‐yl)‐1H‐Indole Derivatives: A New Class of Antimycobacterial Compounds – Conventional Heating in Comparison with MW‐Assisted Synthesis

2‐Aryl‐3‐(1H‐imidazol‐1‐yl and 1H‐1,2,4‐triazol‐1‐yl)‐1H‐indole derivatives were synthesized and tested for their in‐vitro antifungal and antimycobacterial activities. These indole derivatives were devoid of antifungal activity against the tested strains of Candida spp. Yet, they exhibited an interesting antitubercular activity against Mycobacterium tuberculosis reference strain H₃₇Rv.     

Antimycobacterial activity of cyclic dipeptides isolated from Bacillus sp. N strain associated with entomopathogenic nematode

Context: Tuberculosis (TB) is one of the leading causes of morbidity and mortality with a global mortality rate of two million deaths per year; one-third of the world’s population is infected with Mycobacterium tuberculosis.

Objective: The aim of this study was to determine the antimycobacterial activity of six diketopiperazines (DKPs) purified from a Bacillus sp. N strain associated with entomopathogenic nematode Rhabditis (Oscheius) sp.

Materials and methods: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration of DKPs were determined using the broth dilution method on Middlebrook 7H11 against M. tuberculosis H₃₇Rv. Time-kill assay was used to determine the rate of killing of M. tuberculosis H₃₇Rv by DKPs. The cytotoxicity of the DKPs was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay against the VERO cell line.

Results: Out of six DKP-tested cyclo-(d-Pro-l-Leu), cyclo-(l-Pro-l-Met) and cyclo-(d-Pro-l-Phe) recorded antimycobacterial activity, the cyclo-(l-Pro-l-Met) showed the highest activity and MIC values of 4?μg/ml for M. tuberculosis H₃₇Rv. The MIC value for rifampicin was 0.06?μg/ml. Growth curve study by the MIC concentration of cyclic dipeptides recorded significant inhibition when compared with control. Time-kill curve showed maximum reduction of colony count was between 3 and 5 weeks. The DKPs are nontoxic to the VERO cell line up to 200?µg/ml. The antimycobacterial activity of cyclo-(d-Pro-l-Leu), cyclo-(l-Pro-l-Met) and cyclo-(d-Pro-l-Phe) is reported in this study for the first time.

Discussion and conclusion: In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for treatment against TB.     

Structure activity relationship, acute toxicity and cytotoxicity of antimycobacterial neolignan analogues

Objectives The study's aims were to evaluate the antimycobacterial activity of 13 synthetic neolignan analogues and to perform structure activity relationship analysis (SAR). The cytotoxicity of the compound 2‐phenoxy‐1‐phenylethanone (LS‐2, 1 ) in mammalian cells, such as the acute toxicity in mice, was also evaluated. Methods The extra and intracellular antimycobacterial activity was evaluated on Mycobacterium tuberculosis H37Rv. Cytotoxicity studies were performed using V79 cells, J774 macrophages and rat hepatocytes. Additionally, the in‐vivo acute toxicity was tested in mice. The SAR analysis was performed by Principal Component Analysis (PCA). Key findings Among the 13 analogues tested, LS‐2 ( 1 ) was the most effective, showing promising antimycobacterial activity and very low cytotoxicity in V79 cells and in J774 macrophages, while no toxicity was observed in rat hepatocytes. The selectivity index (SI) of LS‐2 ( 1 ) was 91 and the calculated LD50 was 1870 mg/kg, highlighting the very low toxicity in mice. SAR analysis showed that the highest electrophilicity and the lowest molar volume are physical‐chemical characteristics important for the antimycobacterial activity of the LS‐2 ( 1 ). Conclusions LS‐2 ( 1 ) showed promising antimycobacterial activity and very weak cytotoxicity in cell culture, as well as an absence of toxicity in primary culture of hepatocytes. In the acute toxicity study there was an indication of absence of toxicity on murine models, in vivo.     

Synthesis and Antimycobacterial Activity of Azetidine‐, Quinazoline‐, and Triazolo‐thiadiazole‐containing Pyrazines

The re‐emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug‐resistant strains of Mycobacterium tuberculosis, emphasizes the need for the discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of N‐[2‐(substituted aryl)‐3‐chloro‐4‐oxoazetidin‐1‐yl]‐2‐(pyrazin‐2‐yloxy)acetamide, 6‐(substituted aryl)‐3‐[(pyrazin‐2‐yloxy)methyl][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole, and N‐[6‐({2‐[(pyrazin‐2‐yloxy)acetyl] hydrazino}sulfonyl)‐2‐methyl‐4‐oxo‐1,4‐dihydroquinazolin‐3(2H)yl]‐substituted aryl sulfonamides. The compounds were synthesized using the appropriate synthetic route. All synthesized compounds were assayed in vitro for antimycobacterial activity against the H37 Rv strain of Mycobacterium tuberculosis. The minimum inhibitory concentration (MIC) was determined for the test compounds as well as for the reference standards. The compound which exhibited good antimycobacterial activity contains the substituents fluorine and methoxy. These electron‐withdrawing or ‐donating substituents amend the lipophilicity of the test compounds which, in turn, alter the permeability across the bacterial cell membrane. Compounds 28 , 37 , and 43 showed good antimycobacterial activity while compound 51 showed a promising antimycobacterial activity.     

Synthesis and Antimycobacterial Activity of a Novel Series of Isonicotinylhydrazide Derivatives

A novel series of 14 new isonicotinyl hydrazide derivatives 2a – g , 3a – g containing a 4‐thiazolidinone / 2‐azetidinone nucleus were synthesized by reacting N′‐substituted arylidene / heteroarylidene isonicotinyl hydrazide 1a – g with thioglycollic acid in the presence of dry benzene and with chloroacetyl chloride in the presence of triethylamine, respectively. Structures of all newly synthesized compounds were characterized on the basis of elemental analyses and spectral data (IR and ¹H‐NMR). All the title compounds were tested for their in‐vitro antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv using Alamar‐Blue susceptibility test, and the activity is expressed as the minimum inhibitory concentration (MIC) in μg/mL. Among the series, compounds 2b , 2g , 3b , and 3g displayed an encouraging antimycobacterial activity profile as compared to that of the reference drugs isoniazid / rifampicin.     

Substituted Xanthones as Antimycobacterial Agents,Part 2: Antimycobacterial Activity

A series of substituted xanthones was tested for their activity against four mycobacterial strains (Mycobacterium tuberculosis, M. avium, M. lufu, M. smegmatis) by determination of the minimum inhibitory concentrations (MIC values). For the most active compounds, supplementary characterisation was performed by bacterial growth kinetics, which allows a more precise interpretation of their antimycobacterial effects. From the test set, 1-methyl-2,4,7-trinitroxanthone ( 8a ) showed the highest antimycobacterial activity with a MIC value of 3 μg/mL against M. tuberculosis, which is comparable to the effect of well known drugs used in the treatment of tuberculosis. For all other compounds, the MIC values could not be determined, due to the comparatively low activity and to the poor solubility of the compounds, respectively. The semiquantitative evaluation of activity against the different strains of mycobacteria resulted in a classification into three activity classes, which will be used as dependent parameter in QSAR investigations, to be published in Part 3 of this series.     

Antituberculosis activity of hydrazones derived from 4-fluorobenzoic acid hydrazide

A series of substitututed methylene/ethylene 4-fluorophenylhydrazide derivatives (3a–p) was synthesized with the aim of evaluating their antimycobacterial activity toward a strain of Mycobacterium tuberculosis H37Rv. Their chemical structures were confirmed by ¹H-nuclear magnetic resonance (NMR) and electrospray mass spectrometry (ES-MS) spectral data, and elemental analysis. The in vitro antimycobacterial evaluation was performed according to the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) antituberculosis drug discovery program. Compound 3a, 4-fluorobenzoic acid [(2,6-dichlorophenyl) methylene]hydrazide, showed the highest inhibitory activity of all the compounds under study.     

Research on Antifungal and Antimycobacterial Agents. Synthesis and Activity of 4-Alkylthiopyridine-2-carbothioamides

A series of 4-alkylthiopyridine-2-carbothioamides have been prepared and evaluated in vitro for antimicrobial activity. Chemical structures have been demonstrated by IR and ¹H NMR data and by elemental analysis. The antimycobacterial activity of these compounds against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium, and Mycobacterium fortuitum, and the antifungal activity against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Trichophyton mentagrophytes, Aspergillus fumigatus, and Absidia corymbifera were determined by the MIC values. Compounds 3 exhibit good antimycobacterial activity compared to isoniazide. A moderate antifungal activity was observed against T. mentagrophytes. Activity is influenced by hydrophobicity of the alkyl group.     

Antimykobakterielle Eigenschaften von Verbindungen des Phenothiazintyps

Antimycobacterial Properties of Selected Phenothiazines Tests for antimycobacterial properties (Mycobacterium tuberculosis H37 Ra, Middlebrook-7H9-broth) of the phenothiazines 1 – 11 are described. The growth inhibition of these compounds can be blocked by the addition of histamine.