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1.
Venugopala K. Narayanaswamy Susanta K. Nayak Melendhran Pillay Renuka Prasanna Yacoob M. Coovadia Bharti Odhav 《Chemical biology & drug design》2013,81(2):219-227
A series of 2‐(substituted phenyl/benzyl‐amino)‐6‐(4‐chlorophenyl)‐5‐(methoxycarbonyl)‐4‐methyl‐3,6‐dihydropyrimidin‐1‐ium chlorides 7–13 and 15 was synthesized in their hydrochloride salt form. The title compounds were characterized by FT‐IR, NMR (1H and 13C) and elemental analysis. They were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, multidrug resistance tuberculosis and extensively drug resistance tuberculosis by agar diffusion method and tested for the cytotoxic action on peripheral blood mononuclear cells by MTT assay. Among all the tested compounds in the series, compounds 7 and 11 emerged as promising antitubercular agents at 16 μg/mL against multidrug resistance tuberculosis and over 64 μg/mL against extensively drug resistance tuberculosis. The conformational features and supramolecular assembly of the promising compounds 7 and 11 were determined by single crystal X‐ray study. 相似文献
2.
Neha Agre Mihir Khambete Arundhati Maitra Antima Gupta Tulika Munshi Sanjib Bhakta Mariam Degani 《Chemical biology & drug design》2020,95(1):192-199
We report the biological evaluation of 5‐(5‐nitrothiophen‐2‐yl)‐4,5‐dihydro‐1H‐pyrazole derivatives against bacteria, eukaryotic cell lines and the assessment of their mechanisms of action to determine their prospects of being developed into potent antituberculosis agents. The compounds were evaluated for their antibacterial property against Mycobacterium tuberculosis H37Rv, multidrug‐resistant M. tuberculosis, Mycobacterium bovis BCG, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus using high‐throughput spot‐culture growth inhibition assay. They were found to be selective toward slow‐growing mycobacteria and Gram‐positive bacteria. In M. bovis BCG, they exhibited a bactericidal mode of action. Cytotoxicity was assessed in human THP‐1 and murine RAW 264.7 cell lines, and the compounds showed a lower cytotoxicity potential when compared with their antibacterial activity. They were found to be excellent whole‐cell efflux pump inhibitors of the mycobacterial surrogate M. aurum, performing better than known efflux pump inhibitor verapamil. The 5‐nitrothiophene moiety was identified for the first time as a prospective inhibitor scaffold of mycobacterial arylamine N‐acetyltransferase enzyme, which is the key enzyme in metabolizing isoniazid, a first‐line antituberculosis drug. The two aforementioned findings make the compounds potential hits in the development of adjunctive tuberculosis therapy. 相似文献
3.
Barbora Servusova‐Vanaskova Pavla Paterova Vladimir Garaj Jana Mandikova Jiri Kunes Lieve Naesens Petr Jílek Martin Dolezal Jan Zitko 《Chemical biology & drug design》2015,86(4):674-681
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 . 相似文献
4.
Oriana Tabarrini Stefano Sabatini Serena Massari Marco Pieroni Scott G. Franzblau Violetta Cecchetti 《Chemical biology & drug design》2012,80(5):781-786
The screening of an in‐house quinolones library against Mycobacterium tuberculosis (Mtb) H37Rv, followed by a first cycle of optimization, yielded 6‐hydrogen‐8‐methyl derivatives endowed with good potency. The antitubercular activity also encompassed the bacteria in a non‐replicating state (NRP‐TB) with minimum inhibitory concentration values lower than those of the reference agent, moxifloxacin. Among the best compounds, 11w and 11ai , characterized by a properly substituted piperidine at the C‐7 position, were active against single‐drug‐resistant (SDR‐TB) Mtb strains, maintaining overall good potency also against ciprofloxacin‐resistant Mtb. This study expands the body of SAR around antitubercular quinolones leading to reconsider the role played by the usual fluorine atom at the C‐6 position. Further elaboration of the 6‐hydrogen‐8‐methylquinolone scaffold, with a particular focus on the C‐7 position, is expected to give even more potent congeners holding promise for shortening the current anti‐TB regimen. 相似文献
5.
Ranjan C. Khunt Vijay M. Khedkar Evans C. Coutinho 《Chemical biology & drug design》2013,82(6):669-684
Frequency of tuberculosis is progressively increasing worldwide. New emerging strains of bacilli that are emerging are resistant to the currently available drugs which make this issue more alarming. In this regard, a series of substituted quinolinyl chalcones, quinolinyl pyrimidines, and pyridines were synthesized and evaluated for their antitubercular activity in vitro against Mycobacterium tuberculosis H37RV. To establish the role of the 2‐chloroquinoline nucleus as a pharmacophoric group and study its influence on the antimycobacterial activity, a 3D‐QSAR study based on CoMFA and CoMSIA was undertaken on this set of 2‐chloroquinoline derivatives. Statistically significant models that are able to well correlate the antimycobacterial activity with the chemical structures of the 2‐chloroquinolines have been developed. The contour maps resulting from the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction‐field contour maps also showed a high level of internal consistency. The information obtained from the field 3‐D contour maps may be fruitfully utilized in the design of more potent 2‐chloroquinoline‐based analogs as potential antitubercular candidates. 相似文献
6.
Synthesis,biological evaluation,and molecular docking studies of novel 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles derivatives targeting Mycobacterium tuberculosis
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Navnath D. Rode Amol D. Sonawane Laxman Nawale Vijay M. Khedkar Ramesh A. Joshi Anjali P. Likhite Dhiman Sarkar Rohini R. Joshi 《Chemical biology & drug design》2017,90(6):1206-1214
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. 相似文献
7.
K. Hazra L. V. G. Nargund P. Rashmi J. N. Narendra Sharath Chandra B. Nandha M. S. Harish 《Archiv der Pharmazie》2012,345(2):137-146
In an attempt to find a new and a safer drug for tuberculosis, we have synthesized a series of fluoronitrobenzothiazolopyrazolines for antitubercular activity. The series comprises three subclasses: fluorobenzothiazolopyrazolines ( 11a–f ), fluoronitrobenzothiazolopyrazoline, nitro group at 5th position ( 12a–f ) and 4th position ( 13a–f ). All compounds were screened for their in‐vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain by using Middlebrook 7H‐9 broth. An introduction of ? NO2 group at 5th position of benzothiazole ring ( 12a–f ) increased the antitubercular activity whereas introduction of ? NO2 group at 4th position ( 13a–f ) was found to decrease the activity remarkably. Two compounds from each series showing good antitubercular activity were tested for cytotoxicity on THP‐1 cell lines and they showed low cytotoxicity. 相似文献
8.
Daniele Zampieri Maria Grazia Mamolo Erik Laurini Giuditta Scialino Elena Banfi Luciano Vio 《Archiv der Pharmazie》2009,342(12):716-722
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. 相似文献
9.
10.
Study of the Cytotoxic and Bactericidal Effects of Sila‐substituted Thioalkyne and Mercapto‐thione Compounds based on 1,2,3‐Triazole Scaffold
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Hanieh Mousazadeh Morteza Milani Nosratollah Zarghami Effat Alizadeh Kazem D. Safa 《Basic & clinical pharmacology & toxicology》2017,121(5):390-399
A series of sila‐organosulphur compounds containing 1,2,3‐triazole cores were screened for their cytotoxic activity on human breast cancer cell line MCF‐7. Most of the tested compounds exhibited moderate‐to‐good activity against the cancer cells. Especially, the compound 4‐((2‐(trimethylsilyl)ethynylthio)methyl)‐1‐benzyl‐1H‐1,2,3‐triazole ( 3a) from series of sila‐substituted thioalkyne 1,2,3‐triazoles (STATs) and the compounds 3‐(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)‐1‐mercapto‐1,1‐bis(trimethylsilyl)propane‐2‐thione ( 4a) and 1‐mercapto‐1,1‐bis(trimethylsilyl)‐3‐(1‐phenethyl‐1H‐1,2,3‐triazol‐4‐yl)propane‐2‐thione ( 4e) from series of sila‐substituted mercapto‐thione 1,2,3‐triazoles (SMTTs) exhibited promising cytotoxicity against MCF‐7 with IC50 values of 35.17, 32.63 and 30.3 μg/mL, respectively. In addition, the possible mechanisms for inhibition of cell growth and induction of apoptotic cell death were explored by DAPI staining, cell cycle analysis and qRT‐PCR. The synthetic compounds were evaluated for their in vitro antibacterial activities, and as a result, the most prominent effects were observed for 3e and 4e . Especially, 3e was found to be quite active against all the tested strains with the MIC values ranging from 15 to 62 μg/mL, except P. aeruginosa. The results of the time‐kill assay suggested that the compound of 3e completely inhibited the growth of both gram‐negative bacteria, A. baumannii, and gram‐positive bacteria, S. aureus. In addition, SEM analysis confirmed morphostructural damage of the bacteria. Our findings could be applicable for developing dual‐targeting anticancer/antibacterial therapeutics. 相似文献
11.
Suresh Kumar Neeraj Upmanyu Obaid Afzal Sandhya Bawa 《Chemical biology & drug design》2014,84(5):522-530
A series of 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]thiocarbamide and 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]methylthiocarbamide derivatives was synthesized as antitubercular agent. The structure of quinolinyl amines and their thiocarbamide derivatives were established on the basis of IR, 1H and 13C‐NMR and mass spectral data. All the compounds were tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis (ATCC‐25177) in Lowenstein‐Jensen medium by well diffusion method and MIC by twofold serial dilution method. Results of the antitubercular screening revealed that compounds showed moderate to good antitubercular activity. Compound having two halogens in the phenyl rings viz. 3g , 3h , 4g, and 4h exhibited MIC of 50 μg/mL. The computational parameters relevant to absorption and permeation of target compounds were also calculated and found to be well correlated with antitubercular activity. 相似文献
12.
Manishkumar B. Patel Uma Harikrishnan Nikunj N. Valand Nishith R. Modi Shobhana K. Menon 《Archiv der Pharmazie》2013,346(3):210-220
A series of novel cationic fullerene derivatives bearing a substituted‐quinazolin‐4(3H)‐one moiety as a side arm were synthesized using the 1,3‐dipolar cycloaddition reaction of C60 with azomethine ylides generated from the corresponding Schiff bases of substituted quinazolinones. The synthesized compounds 5a – f were characterized by elemental analysis, FT‐IR, 1H NMR, 13C NMR, and ESI‐MS and screened for their antibacterial activity against Mycobacterium tuberculosis (H37RV) and antimicrobial activity against selected Gram‐positive (Staphylococcus aureus and S. pyogenes) and Gram‐negative (Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli) bacterial and fungal strains (Candida albicans, Aspergillus clavatus, and A. niger), respectively. All the compounds exhibited significant activity, with the most effective compounds having MIC values and zones of inhibition comparable to those of standard drugs. 相似文献
13.
Petra Herzigová Vera Klimešová Karel Palát Jarmila Kaustová Hans‐Martin Dahse Ute Möllmann 《Archiv der Pharmazie》2009,342(7):394-404
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. 相似文献
14.
《Chemical biology & drug design》2018,92(1):1315-1323
In the quest for new active molecules against Mycobacterium tuberculosis, a series of dihydroquinoline derivatives possessing triazolo substituents were efficiently synthesized using click chemistry. The structure of 6l was evidenced by X‐ray crystallographic study. The newly synthesized compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The compounds 6a , 6g, and 6j (MIC: 3.13 μg/ml) showed promising activity when compared to the first‐line drug such as ethambutol. In addition, the structure and antitubercular activity relationship were further supported by in silico molecular docking studies of the active compounds against 3IVX.PDB (crystal structure of pantothenate synthetase in complex with 2‐(2‐(benzofuran‐2‐ylsulfonylcarbamoyl)‐5‐methoxy‐1H‐indol‐1‐yl)acetic acid). 相似文献
15.
Synthesis and Antimicrobial Activity of 4‐Chloro‐3‐Nitrophenylthiourea Derivatives Targeting Bacterial Type II Topoisomerases
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Anna Bielenica Karolina Stępień Agnieszka Napiórkowska Ewa Augustynowicz‐Kopeć Sylwester Krukowski Marta Włodarczyk Marta Struga 《Chemical biology & drug design》2016,87(6):905-917
A series of novel 4‐chloro‐3‐nitrophenylthiourea derivatives were synthesized and evaluated for their antimicrobial, antibiofilm and tuberculostatic activities. Most of compounds exhibited high antibacterial activity against both standard and hospital strains (MIC values 0.5–2 μg/mL), as compared to Ciprofloxacin. Derivatives with 3,4‐dichlorophenyl ( 11 ) and 3‐chloro‐4‐methylphenyl ( 13 ) substituents were the most promising towards Gram‐positive pathogens. Both of them exhibited antibiofilm potency and effectively inhibited the formation of biofilms of methicillin‐resistant and standard strains of Staphylococcus epidermidis. Two N‐alkylthioureas ( 20, 21 ) showed twofold to fourfold increase in in vitro potency against isolates of Mycobacterium tuberculosis, as compared to Isoniazid. An action of 7, 10 , 11, 13, 20 and 21 against activity of topoisomerases isolated from Staphylococcus aureus was studied. Synthesized compounds were found as non‐genotoxic. 相似文献
16.
Design,synthesis, and evaluation of new α‐aminonitrile‐based benzimidazole biomolecules as potent antimicrobial and antitubercular agents
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17.
Design,synthesis, and in vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐oxadiazole derivatives
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Yasodakrishna Sajja Sowmya Vanguru Hanmanth Reddy Vulupala Lingaiah Nagarapu Yogeswari Perumal Dharmarajan Sriram Jagadeesh Babu Nanubolu 《Chemical biology & drug design》2017,90(4):496-500
A new antitubercular agents, benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐ oxadiazole hybrids ( 6a–o ), have been designed and synthesized involving oxidative cyclization of hydrazones by use of di(acetoxy)iodobenzene, characterized by IR,1H NMR,13C NMR, and HRMS, and further confirmed by X‐ray analysis. All the newly synthesized compounds 4a–o evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Among the compounds tested, the compounds 4o (MIC: 1.56 μg/ml) and 4l, 4m (MIC: 3.125 μg/ml) are promising lead analogues and have shown lower cytotoxicity. 相似文献
18.
Biofilm Eradication Kinetics of the Ultrashort Lipopeptide C12‐OOWW‐NH2 Utilizing a Modified MBEC Assay™
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In this study, we report the antimicrobial planktonic and biofilm kill kinetics of ultrashort cationic lipopeptides previously demonstrated by our group to have a minimum biofilm eradication concentration (MBEC) in the microgram per mL (μg/mL) range against clinically relevant biofilm‐forming micro‐organisms. We compare the rate of kill for the most potent of these lipopeptides, dodecanoic (lauric) acid‐conjugated C12‐Orn‐Orn‐Trp‐Trp‐NH2 against the tetrapeptide amide H‐Orn‐Orn‐Trp‐Trp‐NH2 motif and the amphibian peptide Maximin‐4 via a modification of the MBEC Assay? for Physiology & Genetics (P&G). Improved antimicrobial activity is achieved upon N‐terminal lipidation of the tetrapeptide amide. Increased antimicrobial potency was demonstrated against both planktonic and biofilm forms of Gram‐positive micro‐organisms. We hypothesize rapid kill to be achieved by targeting of microbial membranes. Complete kill against established 24‐h Gram‐positive biofilms occurred within 4 h of exposure to C12‐OOWW‐NH2 at MBEC values [methicillin‐resistant Staphylococcus epidermidis (ATCC 35984): 15.63 μg/mL] close to the values for the planktonic minimum inhibitory concentration (MIC) [methicillin‐resistant Staphylococcus epidermidis (ATCC 35984): 1.95 μg/mL]. Such rapid kill, especially against sessile biofilm forms, is indicative of a reduction in the likelihood of resistant strains developing with the potential for quicker resolution of pathogenic infection. Ultrashort antimicrobial lipopeptides have high potential as antimicrobial therapy. 相似文献
19.
Synthesis and in vitro investigation of halogenated 1,3‐bis(4‐nitrophenyl)triazenide salts as antitubercular compounds
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《Chemical biology & drug design》2018,91(2):631-640
The diverse pharmacological properties of the diaryltriazenes have sparked the interest to investigate their potential to be repurposed as antitubercular drug candidates. In an attempt to improve the antitubercular activity of a previously constructed diaryltriazene library, eight new halogenated nitroaromatic triazenides were synthesized and underwent biological evaluation. The potency of the series was confirmed against the Mycobacterium tuberculosis lab strain H37Ra, and for the most potent derivative, we observed a minimal inhibitory concentration of 0.85 μm . The potency of the triazenide derivatives against M. tuberculosis H37Ra was found to be highly dependent on the nature of the halogenated phenyl substituent and less dependent on cationic species used for the preparation of the salts. Although the inhibitory concentration against J774A.1 macrophages was observed at 3.08 μm , the cellular toxicity was not mediated by the generation of nitroxide intermediate as confirmed by electron paramagnetic resonance spectroscopy, whereas no in vitro mutagenicity could be observed for the new halogenated nitroaromatic triazenides when a trifluoromethyl substituent was present on both the aryl moieties. 相似文献
20.
Mahesh Palkar Malleshappa Noolvi Ramappa Sankangoud Veeresh Maddi Andanappa Gadad Laxmi Venkat G. Nargund 《Archiv der Pharmazie》2010,343(6):353-359
Benzothiazole and imidazole compounds are extensively studied heterocyclics due to their wide spectrum of bioactivities. Among them, the imidazo(2,1‐b)‐benzothiazole derivatives are pharmacologically important because of their immunostimulant, anti‐inflammatory, antifungal, antimicrobial, antitumor, and other activities. In the present research work, a novel series of 2,3‐diaryl‐substituted imidazo(2,1‐b)‐benzothiazoles 13a–o have been synthesized by reaction of substituted 2‐aminobenzothiazoles 1–8 and an appropriately substituted α‐bromo‐1‐(4′′‐substituted)‐phenyl‐2‐(4′‐substituted)‐phenyl‐1‐ethanones 9–12 in the presence of anhydrous acetonitrile. They were characterized by physicochemical, elemental, and spectral (IR, 1H‐NMR, and Mass) data. All the synthesized compounds were screened for their in‐vitro antibacterial activity against Gram‐positive, Gram‐negative bacteria. The investigation of antibacterial screening data revealed that most of the compounds tested have demonstrated congruent activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa as compared with the standard ampicillin. Among the series, compounds 13d , 13h , and 13m exhibited excellent an antibacterial activity profile as compared with the standard. In summary, preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activities and they warrant more consideration as prospective antimicrobials. 相似文献