Synthesis and antimycobacterial evaluation of substituted pyrazinecarboxamides

Unsubstituted, halogenated and/or alkylated pyrazine-2-carboxylic acid amides connected via -CONH- bridge with substituted anilines were synthesized using currently known synthetic pathways. The synthetic approach, analytical, spectroscopic, lipophilicity and biological data of 20 newly synthesized compounds are presented. Structure-activity relationships among the chemical structures, the antimycobacterial, antifungal, photosynthesis inhibiting and antialgal activity of the evaluated substituted N-phenylpyrazine-2-carboxamides are discussed. 5-tert-Butyl-6-chloro-N-(3-trifluoromethylphenyl)pyrazine-2-carboxamide (19) has shown the highest activity against Mycobacterium tuberculosis H(37)Rv (MIC=3.13 microg/mL). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for N-(3-trifluoromethylphenyl)pyrazine-2-carboxamide (14, MIC=62.5 micromol/mL). The highest reduction of chlorophyll content in Chlorella vulgaris was found for pyrazine-2-carboxylic acid (3-trifluoromethylphenyl)amide (9, IC(50)=12.1 micromol/L).     

Synthesis of amidine and amide derivatives and their evaluation for anti-inflammatory and analgesic activities

A number of amidine derivatives (2a-i) have been synthesized by condensation of 2-cyanopyridine with various 3,4-diaryl-2-imino-4-thiazolines. Various amide derivatives (3a-h) were synthesized by condensation of orotic acid and hydantoin-5-acetic acid with a number of 3,4-diaryl-2-imino-4-thiazolines using microwave irradiation. All the compounds i.e. (2a-i) and (3a-h) synthesized were characterized by spectroscopic means and elemental analysis. Compounds (2a-i) and (3a-h) at 50 mg/kg p.o. were screened for anti-inflammatory activity whereas 2a-d, f, g, i and 3a, b, d, f at 50 mg/kg p.o. were evaluated for analgesic activity. Compounds 2e and 3g exhibited good anti-inflammatory activity (49% and 34%, respectively) and 2f, g showed interesting (50% in each case) analgesic activity.     

Synthesis and antimycobacterial activities of novel 6-nitroquinolone-3-carboxylic acids

Various 1-(substituted)-1,4-dihydro-6-nitro-4-oxo-7-(sub-secondary amino)-quinoline-3-carboxylic acids were synthesized from 2,4-dichlorobenzoic acid by six step synthesis. The compounds were evaluated for antimycobacterial in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the 48 synthesized compounds, 7-(4-((benzo[d][1,3]dioxol-5-yl)methyl)piperazin-1-yl)-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxoquinoline-3-carboxylic acid (8c) was found to be the most active compound in vitro with MIC of 0.08 and 0.16 microM against MTB and MDR-TB, respectively. In the in vivo animal model 8c decreased the bacterial load in lung and spleen tissues with 2.78 and 4.15-log10 protections, respectively, at the dose of 50 mg/kg body weight.     

Synthesis, anti-tubercular activity and 3D-QSAR study of coumarin-4-acetic acid benzylidene hydrazides

A set of 25 coumarin-4-acetic acid benzylidene hydrazides were synthesized and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H(37)Rv strain using the BACTEC 460 system to determine percentage inhibition. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). Several statistically significant CoMFA models were generated. The CoMFA model generated with database alignment was the best in terms of overall statistics. The CoMFA contours provide a good insight into the structure activity relationships of the compounds reported herein.     

Synthesis, antibacterial and antitubercular activities of some 7-[4-(5-amino-[1,3,4]thiadiazole-2-sulfonyl)-piperazin-1-yl] fluoroquinolonic derivatives

In the present study, a series of 7-[4-(5-amino-1,3,4 thiadiazole-2-sulfonyl)]-1-piperazinyl fluoroquinolonic derivatives VIIa-d were synthesized in good yields and characterized by IR, (1)H-NMR, (13)C-NMR, FAB Mass spectral and elemental analyses. The compounds were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria and selected compounds VIIa, b were screened for antitubercular activity against Mycobacterium tuberculosis H(37)Rv strain by broth dilution assay method. The antibacterial data of the tested N-sulfonylfluoroquinolones VIIa-d indicated that all the synthesized compounds showed better activity against Gram-positive bacteria S. aureus, E. faecelis, Bacillus sp. (MIC=1-5 microg ml(-1), respectively) compared to reference drugs. The MIC values of tested derivatives connotes that the sparfloxacin and gatifloxacin derivatives VIIc, d were most active against the tested Gram-positive bacterial strains (MIC=1-5 microg ml(-1)). All the tested compounds VIIa-d showed poor activity against the Gram-negative bacteria. The in vitro antitubercular activity reports of selected compounds VIIa, b against M. tuberculosis strain H(37)Rv showed moderate activity at MIC of 10 microg ml(-1).     

Amide isosteres in structure-activity studies of antibacterial minor groove binders

Antibacterial minor groove binders related to the natural product, distamycin, are development candidates for novel antibiotics. Alkenes have been found to be effective substitutes for the isosteric amide links in some positions and alkyl groups larger than methyl have been found to increase binding to DNA in both selectivity and affinity. However the impact of other isosteres such as diazenes and the position of an alkyl group with respect to DNA binding and antibacterial activity are not known. The effects of some systematic variations in the structure of polyamide minor groove binders are investigated. Isosteres of the amide link (alkenes and diazenes) are compared: it is shown that all three are competent for binding to DNA but that alkene links give the tightest binding and highest antibacterial activity; no significant antibacterial activity was found for compounds with a diazene link. Within a series of alkene linked compounds, the effect of branched N-alkyl substituents on binding to DNA and antibacterial activity is investigated: it was found that C3 and C4 branched chains are acceptable at the central pyrrole residue but that at the pyrrole ring adjacent to the basic tail group, a C4 branched chain was too large both for DNA binding and for antibacterial activity. The active branched alkyl chain compounds were found to be especially active against Mycobacterium aurum, a bacterium related to the causative agent of tuberculosis.     

Novel bradykinin-1 antagonists containing a (1,2,3,4-tetrahydro-isoquinolin-1-yl)acetic acid scaffold

A novel B(1) antagonist core was utilized and the effects of modification of its amide side chain on the biological activity were tested. The imino functional group of isoquinolin-1-ylacetic acid and its 6,7-dimethoxy variant was sulfonylated (4-toluenesulfonyl), while the acetyl side chain was converted to amides. Three of the synthesized compounds exhibited significant activity at the recombinant human B(1) receptors in binding tests and also in a functional assay.     

Synthesis, antiarrhythmic and anticoagulant activities of novel thiazolo derivatives from methyl 2-(thiazol-2-ylcarbamoyl)acetate

A series of novel thiazolo derivatives were synthesized by initial condensation of methyl 2-(thiazol-2-ylcarbamoyl)acetate with phenyl isothiocyanate and further reactions using different organic reagents. The structures of newly synthesized compounds were confirmed by IR, 1H NMR, EIMS spectral data and elemental analysis. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). All the compounds were screened for their antiarrhythmic and anticoagulant activities and they showed high antiarrhythmic activity compared with procaine amide and lidocaine as positive controls. The detailed synthesis, spectroscopic data, LD(50) and pharmacological activities of the synthesized compounds were reported.     

Synthesis and antitubercular activity of 3-aryl substituted-2-[1H(2H)benzotriazol-1(2)-yl]acrylonitriles

A series of 22 3-aryl substituted-2-(1H(2H)-benzotriazol-1(2)-yl)acrylonitriles was synthesized for a preliminary in vitro evaluation of antitubercular activity according to an international program with the Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF). This work reports the synthetic approach and analytical and spectroscopic characterization (UV, IR, 1H- and 13C-NMR) of all compounds synthesized. Several compounds showed an interesting activity in the preliminary screening with a percent growth inhibition of the virulent Mycobacterium tuberculosis between 40 and 99% at the concentration of 12.5 microg/mL. The most effective derivatives E-5a and E-5e were also tested against M. avium in vitro.     

New quinolin-4-yl-1,2,3-triazoles carrying amides, sulphonamides and amidopiperazines as potential antitubercular agents

Three new series of quinoline-4-yl-1,2,3-triazoles carrying amides, sulphonamides and amidopiperazines were synthesized through multi-step reactions. The required intermediate, [1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methanol (2) was prepared by treating 4-azido-6-methoxy-2-methylquinoline (1) with propargyl alcohol. Three different series of compounds were synthesized from this intermediate. All the newly synthesized compounds were characterized by spectral and elemental analyses. The structure of 2 was confirmed by X-ray crystallographic study. Further, the title compounds were evaluated for their in vitro anti-bacterial activity against five different bacterial strains and antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis (ATCC 19420) and Mycobacterium fortuitum (ATCC 19542). Title compounds, 6a, 6d, 6i, 6j, 7e, 10a and 10i were found to be active against Mycobacterium tuberculosis H37Rv strain and could be lead molecules of interest.     

Preparation and in vitro evaluation of benzylsulfanyl benzoxazole derivatives as potential antituberculosis agents

A set of 2-benzylsulfanyl derivatives of benzoxazole was synthesized and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis, non-tuberculous mycobacteria and multidrug-resistant M. tuberculosis. The activities were expressed as the minimum inhibitory concentration (MIC) in mmol/L. The substances showed similar activity against all tested strains. The lead compounds in the set, dinitro derivatives exhibited significant activity against both sensitive and resistant strains of M. tuberculosis and also against non-tuberculous mycobacteria. To facilitate drug design of benzoxazole as potential antituberculosis agent, we have explored the quantitative structure-activity relationship (QSAR). We demonstrated that lower lipophilicity has significant contribution to activity. Dinitrobenzylsulfanyl derivative of benzoxazole represents the promising small-molecule synthetic antimycobacterials.     

Synthesis and biological evaluation of amide derivatives of (5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)acetic acid as anti-inflammatory agents with reduced gastrointestinal ulcerogenecity

A variety of amide derivatives of (5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)acetic acid were synthesized and screened for their analgesic and anti-inflammatory activities. The compounds were found to have longer activity profile exceeding that of indomethacin in carrageenan-induced rat paw edema model. Few selected compounds were also screened for their antipyretic, anti-arthritic and ulcerogenecity potential. From these studies it can be concluded that these compounds though have significant antipyretic activity did not act through the inhibition of TNF-alpha. The test compounds failed to prevent the development of secondary inflammation in adjuvant-induced arthritis assay. However, these compounds showed no ulcer formation at the tested dose level of 100 mg/kg p.o.     

Synthesis and characterization of novel hydrazide-hydrazones and the study of their structure-antituberculosis activity

A series of hydrazide-hydrazones, based on a series of 4-substituted benzoic acid, were synthesized, and their structures were elucidated and screened for the antituberculosis activity against Mycobacterium tuberculosis H37Rv with the help of the BACTEC 460 radiometric system. Compound 3, 4-fluorobenzoic acid [((5-nitro)thiophen-2yl) methylene]hydrazide showed the highest inhibitory activity in this series. The search of pharmacophores was done by means of the Electronic-Topological Method (ETM). The model developed in this study is supposed to be applied to the design, preparation and screening of new compounds of similar structure in order to further test and optimize the model with the eventual goal of preparing new anti-tubercular agents.     

Synthesis and biological activity of 4-thiazolidinones, thiosemicarbazides derived from diflunisal hydrazide

Two novel series of 4-thiazolidinone derivatives, namely 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid [2-(5-nitro-2-furyl/substituted phenyl)-4-thiazolidinone-3-yl]amides (5a-g) and 2-(2',4'-difluoro-4-hydroxybiphenyl-3-carbonylhydrazono)-3-alkyl/aryl-4-thiazolidinones (6a-e) together with 5-(2',4'-difluoro-4-hydroxybiphenyl-5-yl)-2-cyclohexylamino-1,3,4-oxadiazole (7a) have been synthesized as title compounds. 1-(2',4'-Difluoro-4-hydroxybiphenyl-3-carbonyl)-4-alkyl/arylthiosemicarbazides (4a-g) were also obtained and used as intermediate to give the title compounds. All synthesized compounds were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, antiviral and antimicrobial activities against various virus, bacteria and fungi strains.     

Structural analysis of inhibition of Mycobacterium tuberculosis methionine aminopeptidase by bengamide derivatives

Natural product-derived bengamides possess potent antiproliferative activity and target human methionine aminopeptidases for their cellular effects. Using bengamides as a template, several derivatives were designed and synthesized as inhibitors of methionine aminopeptidases of Mycobacterium tuberculosis, and initial antitubercular activity were observed. Here, we present three new X-ray structures of the tubercular enzyme MtMetAP1c in complex with the inhibitors in the Mn(II) form and in the Ni(II) form. All amide moieties of the bengamide derivatives bind to the unique shallow cavity and interact with a flat surface created by His-212 of MtMetAP1c in the Mn(II) form. However, the active site metal has significant influence on the binding mode, because the amide takes a different conformation in the Ni(II) form. The interactions of these inhibitors at the active site provide the structural basis for further modification of these bengamide inhibitors for improved potency and selectivity.     

Synthesis, structural activity relationship and anti-tubercular activity of novel pyrazoline derivatives

In the present investigation, a series of 5-(-4-(substituted) phenyl)-3-(4-hydroxy-3-methylphenyl)-4,5-dihydro-1H-1-pyrazolyl-2-toluidino methane thione and 5-(substituted) phenyl-3-(4-hydroxy-3-methylphenyl)-4,5-dihydro-1H-1-pyrazolyl-2-methoxyanilino methane thione were synthesized by the reaction between hydrazine hydrate and chalcones (3a-k) followed by condensation with appropriate aryl isothiocyanate which yielded N-substituted pyrazoline derivatives. Newly synthesized compounds were tested for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. Among the synthesized compounds, compound anilino-3-(4-hydroxy-3-methylphenyl)-5-(2,6-dichlorophenyl)-4,5-dihydro-1H-1-pyrazolylmethanethione (6i) was found to be more active agent against M. tuberculosis H37Rv with minimum inhibitory concentration of 0.0034 microM.     

Synthesis and anti-mycobacterial activity of novel amino alcohol derivatives

Thirteen new hydroxyethylamines have been synthesized from reactions of (2S,3S)Boc-phenylalanine epoxide, piperonylamine and arenesulfonyl chlorides in good yields. These compounds were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in μM. Two amino alcohols displayed significant activity when compared with first line drug ethambutol (EMB). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of tuberculosis.     

Design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents

4-acetamide Pyrazolone 2 was synthesized by acetylation of 4-amino antipyrine 1 in excellent yield. 4-acetamide pyrazolone 2 was exploited as a starting material for the syntheses of hitherto unknown different types of new heterocyclic compounds incorporating the antipyrine moiety which expect highly biological activity against various microorganisms. Thus, Claisen condensation of 4-acetamide pyrazolone 2 with diethyl oxalate have been utility to afford new 4-oxaloacetyl antipyrine 3, which upon hydrazinolysis of the ester function to obtain the acetohydrazide derivative 18 which used as starting material to synthesize 1,2,4-triazol 19 and hydrazone 20 derivatives. 4-aminothiophene carboxylate derivatives 6, 7 were synthesized by utility of Gewald reaction. On the other hand, Michael type addition of the enolate ion of acetyl functions in acetamide pyrazolone 2 to the activated double bond in arylidenemalonoester to furnish pyrane derivative 9 was done. Finally, 4-acetamide pyrazolone 2 was treated with aromatic substituted aldehyde to exhibit thiophenacrylamide derivative 10. Compound 6 gave characteristic reaction for enaminonitriles, thus, the behavior of o-aminoester of 4-aminothiophene carboxylate derivative 6 toward electrophilic reagent, one carbon donars, amide and acid was also investigated to afford the correspondence thiophene derivatives 11,12,13,15 and 16. In addition, treatment of carboxamide derivative 16 with thionyl chloride afforded the thienothiadiazine derivative 17. The characterization of all synthesized compounds was done by elemental analysis and spectral studies. Moreover, all the synthesized compounds were tested against antimicrobial activities by the disc diffusion method, which exhibited higher promising biological activities.     

1,8-Naphthyridines VI. Synthesis and anti-inflammatory activity of 5-(alkylamino)-N,N-diethyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides with a new substitution pattern on the triazole ring

On the basis of the good anti-inflammatory properties shown by the 9-alkyl-N,N-dialkyl-5-(alkylamino)[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 1, a series of analogues of such compounds, in which the 9-alkyl substituent was replaced by an ester or amide group (compounds 3a-i), was prepared and tested (inhibition of carrageenan-induced paw edema in the rat). Also two 5-(N-alkyl,N-acylamino) derivatives (compounds 4a,b) were synthesized and evaluated for the same purpose. Even though the general trend for these new [1,2,4]triazolo[4,3-a][1,8]naphthyridine derivatives was a decrease in activity compared with compounds 1, some of the new synthesized compounds exhibited still good anti-inflammatory properties.     

Synthesis of new 4-pyrrol-1-yl benzoic acid hydrazide analogs and some derived oxadiazole, triazole and pyrrole ring systems: a novel class of potential antibacterial and antitubercular agents

In the present study, a novel series of 4-pyrrol-1-yl benzoic acid hydrazide analogs, some derived 5-substituted-2-thiol-1,3,4-oxadiazoles, 5-substituted-4-amino-1,2,4-triazolin-3-thione and 2,5-dimethyl pyrroles have been synthesized in good yields and characterized by IR, NMR, mass spectral and elemental analyses. Compounds were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria and compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain by broth dilution assay method. Some compounds showed very good antibacterial and antitubercular activities.