Antituberculotic 4'-Cyclohexylthiobenzanilides: Combination of Free-Wilson Method in QSAR with Topliss Approach

1993 ◽  
Vol 58 (1) ◽  
pp. 205-212 ◽  
Author(s):  
Karel Waisser ◽  
Lenka Kubicová ◽  
Želmíra Odlerová
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimycobacterial Activity ◽  
Significant Activity ◽  
Mycobacterium Kansasii ◽  
Type Analysis ◽  
Qsar Analysis ◽  
Preliminary Study

On the basis of a preliminary study of antimycobacterial activity of thiobenzanilides against Mycobacterium kansasii, a group of 4'-cyclohexylthiobenzanilids have been prepared which exhibit a significant activity against the microorganism mentioned. The whole set of 35 thiobenzanilides was tested with Mycobacterium tuberculosis, and on the basis of QSAR analysis conclusions have been made with regard to prognostics of structures suitable for further studies. The problem was solved by the method by Free and Wilson combined with the Topliss approach and by a Hansch type analysis.

Combination of the Topliss Approach with the Free-Wilson Analysis in the Study of Antimycobacterial Activityof 4-Alkylthiobenzanilides

1997 ◽  
Vol 62 (9) ◽  
pp. 1503-1510 ◽  
Author(s):  
Jiří Kuneš ◽  
Jiří Jáchym ◽  
Petr Jirásko ◽  
Želmíra Odlerová ◽  
Karel Waisser
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Avium ◽  
Steric Effect ◽  
Antimycobacterial Activity ◽  
Mycobacterium Fortuitum ◽  
Mycobacterium Kansasii ◽  
Isopropyl Group ◽  
Butyl Group ◽  
Preliminary Study ◽  
Cyclohexyl Group

On the basis of a preliminary study of the antimycobacterial activity of thiobenzanilides, a group of 4'-isopropyl- and 4'-butylthiobenzanilides have been synthesized and tested against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium and Mycobacterium fortuitum. The effect of the substituents on minimum inhibitory concentrations was calculated by the Free-Wilson method. The separated values were analyzed by the Topliss approach. The substitution of the thiobenzanilide in position 4' by the isopropyl group or butyl group increased the antimycobacterial activity less than the cyclohexyl group. The substitution in position 4 decreased the activity by the steric effect.

scholarly journals SYNTHESIS AND ANTITUBERCULAR ACTIVITY OF PIPERIDINE AND MORPHOLINE 1, 8 NAPHTHYRIDINE ANALOGUES

2016 ◽  
Vol 8 (12) ◽  
pp. 252 ◽  
Author(s):  
Muwaffag Badawneh ◽  
Jalal Aljamal
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inhibitory Concentration ◽  
Antitubercular Activity ◽  
Antimycobacterial Activity ◽  
Significant Activity ◽  
Reference Drug ◽  
Novel Drugs ◽  
Elemental Analyses ◽  
Antimycobacterial Agents

<p><strong>Objective: </strong>The search for new, potentially useful antimycobacterial agents. In continuation with our previous screening for the discovery of novel drugs for tuberculosis, a new series of 1,8-naphthyridines derivatives were synthesized and evaluated <em>in vitro </em>for antimycobacterial activity against <em>Mycobacterium tuberculosis </em>H37Rv.</p><p><strong>Methods: </strong>Several 4-morpholinomethyl-1.8-naphthyridine derivatives have been synthesized in excellent yields. The synthesized compounds were characterized by spectroscopic methods as well as elemental analyses. They were screened for their antimycobacterial activity. The growth was monitored radiometrically in 7H12 broth with the BACTEC 460 TB system. The minimum inhibitory concentration (MIC) was determined for compounds that demonstrated ≥ 90% growth inhibition in the primary screening.</p><p><strong>Results: </strong>The obtained data suggested that all compounds showed significant activity against <em>Mycobacterium tuberculosis </em>H37Rv<em> </em>compared to the standard reference drug. Analogues (6-11) having heterocyclic groups in position 7 were the most potent of those we tested.</p><p><strong>Conclusion: </strong>These findings clearly identify the 1,8-naphthyridine analogue (10) with a 6-amino-2-(4'-methoxy benzylamine-4-morpholinomethyl-7-morpholino-substituent as promising anti-tubercular agents possessing significant activity against <em>Mycobacterium tuberculosis </em>H37Rv</p>

Relationships Between the Chemical Structure of Substances and Their Antimycobacterial Activity Against Atypical Strains. Part 18. 3-Phenyl-2H-1,3-benzoxazine-2,4(3H)-diones and Isosteric 3-Phenylquinazoline-2,4(1H,3H)-diones

1999 ◽  
Vol 64 (11) ◽  
pp. 1902-1924 ◽  
Author(s):  
Karel Waisser ◽  
Miloš Macháček ◽  
Hynek Dostál ◽  
Jiří Gregor ◽  
Lenka Kubicová ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Chemical Structure ◽  
Nontuberculous Mycobacteria ◽  
Antimycobacterial Activity ◽  
Diffusion Method ◽  
Significant Activity ◽  
Vector Algebra ◽  
Phenyl Rings ◽  
Agar Diffusion Method ◽  
Atypical Strains

A series of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones 2 and 3-phenylquinazoline-2,4(1H,3H)-diones 5 substituted on the phenyl rings were synthesized. The target compounds as well as the intermediates were tested against Mycobacterium tuberculosis, M. kansasii, and M. avium. The replacement of the oxygen atom by nitrogen resulted in a decrease or loss of antimycobacterial activity. 2-[(Ethoxycarbonyl)amino]benzanilides 4 appeared to be inactive. Salicylanilides 1 and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones 2 exhibit significant activity against both M. tuberculosis and nontuberculous mycobacteria (the MICs within the range of 4-250 μmol/l for all compounds). The antimycobacterial activity of the compounds increases with increasing both electron-withdrawing properties and hydrophobicity of the substituent(s) on the phenyl moiety. The antimycobacterial profile of the compounds was analyzed according to the criteria based on vector algebra, such as cosine coefficients. Moreover, salicylanilides 1 exhibit activity against other microorganisms tested by the agar diffusion method.

On the Relationship between the Structure and Antimycobacterial Activity of Substituted N-Benzylsalicylamides

2003 ◽  
Vol 68 (7) ◽  
pp. 1275-1294 ◽  
Author(s):  
Karel Waisser ◽  
Milan Peřina ◽  
Věra Klimešová ◽  
Jarmila Kaustová
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Avium ◽  
Antimycobacterial Activity ◽  
Acyl Moiety ◽  
Mycobacterium Kansasii ◽  
Hammett Constants ◽  
Substituent Constants ◽  
The Relationship ◽  
Lipophilicity Parameters

Sixty-six N-benzylsalicylamides substituted in the acyl moiety in positions 3, 4 or 5 and in position 4 on the benzylic aromatic ring were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. To evaluate structure-antimycobacterial activity relationships (QSARs), approaches based on the Free-Wilson as well as a combination of the Free-Wilson and Hansch methods were employed (substituent constants were used to describe the influence of the benzyl substituents, indicator parameters were used for the substituents on the acyl moiety). The use of the Hammett constants for benzyl substituents was not important for QSAR equations. The quadratic representation of lipophilicity parameters (π2) was significant only in QSAR equations of antimycobacterial activity against M. avium.

New Groups of Potential Antituberculotics: Bis(1-aryltetrazol-5-yl) Disulfides. Structure Activity Relationship

1994 ◽  
Vol 59 (1) ◽  
pp. 234-238 ◽  
Author(s):  
Karel Waisser ◽  
Jiří Kuneš ◽  
Alexandr Hrabálek ◽  
Želmíra Odlerová
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Antimycobacterial Activity ◽  
Activity Relationship ◽  
Active Derivative ◽  
Structure Activity ◽  
Medium Activity ◽  
Substituent Constants ◽  
Atypical Strains

Oxidation of 1-aryltetrazole-5-thiols afforded bis(1-aryltetrazol-5-yl) disulfides. The compounds were tested for antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, M. avium and M. fortuitum. In the case of M. tuberculosis, the logarithm of minimum inhibitory concentration showed a parabolic dependence on hydrophobic substituent constants. Although the compounds exhibited low to medium activity, the most active derivative, bis(4-chlorophenyltetrazol-5-yl) disulfide (III) was more effective against atypical strains than are the commercial tuberculostatics used as standards.

scholarly journals Biofilm formation in the lung contributes to virulence and drug tolerance of Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Poushali Chakraborty ◽  
Sapna Bajeli ◽  
Deepak Kaushal ◽  
Bishan Dass Radotra ◽  
Ashwani Kumar
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Biofilm Formation ◽  
Antimycobacterial Activity ◽  
Drug Tolerance ◽  
Host Immune System ◽  
Tissue Sections ◽  
Slow Growing

AbstractTuberculosis is a chronic disease that displays several features commonly associated with biofilm-associated infections: immune system evasion, antibiotic treatment failures, and recurrence of infection. However, although Mycobacterium tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains unclear whether biofilms are formed during infection in vivo. Here, we demonstrate the formation of Mtb biofilms in animal models of infection and in patients, and that biofilm formation can contribute to drug tolerance. First, we show that cellulose is also a structural component of the extracellular matrix of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then, we use cellulose as a biomarker to detect Mtb biofilms in the lungs of experimentally infected mice and non-human primates, as well as in lung tissue sections obtained from patients with tuberculosis. Mtb strains defective in biofilm formation are attenuated for survival in mice, suggesting that biofilms protect bacilli from the host immune system. Furthermore, the administration of nebulized cellulase enhances the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting a role for biofilms in phenotypic drug tolerance. Our findings thus indicate that Mtb biofilms are relevant to human tuberculosis.

In vitro synergistic interactions of oleanolic acid in combination with isoniazid, rifampicin or ethambutol against Mycobacterium tuberculosis

2010 ◽  
Vol 59 (5) ◽  
pp. 567-572 ◽  
Author(s):  
Fa Ge ◽  
Fanli Zeng ◽  
Siguo Liu ◽  
Na Guo ◽  
Haiqing Ye ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Oleanolic Acid ◽  
Antimycobacterial Activity ◽  
Vero Cells ◽  
Drug Resistant ◽  
Synergistic Interactions ◽  
Combination Treatments ◽  
Low Cytotoxicity ◽  
Drug Resistant Strains

Reports have shown that oleanolic acid (OA), a triterpenoid, exists widely in food, medicinal herbs and other plants, and that it has antimycobacterial activity against the Mycobacterium tuberculosis strain H37Rv (ATCC 27294). In this study it was found that OA had antimycobacterial properties against eight clinical isolates of M. tuberculosis and that the MICs of OA against drug-sensitive and drug-resistant isolates were 50–100 and 100–200 μg ml−1, respectively. The combination of OA with isoniazid (INH), rifampicin (RMP) or ethambutol (EMB) showed favourable synergistic antimycobacterial effects against six drug-resistant strains, with fractional inhibitory concentration indices of 0.121–0.347, 0.113–0.168 and 0.093–0.266, respectively. The combination treatments of OA/INH, OA/RMP and OA/EMB displayed either a synergistic interaction or did not show any interaction against two drug-sensitive strains. No antagonism resulting from the OA/INH, OA/RMP or OA/EMB combination was observed for any of the strains tested. OA exhibited a relatively low cytotoxicity in Vero cells. These results indicate that OA may serve as a promising lead compound for future antimycobacterial drug development.

scholarly journals Ambroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Seong Won Choi ◽  
Yuexi Gu ◽  
Ryan Scott Peters ◽  
Padmini Salgame ◽  
Jerrold J. Ellner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimycobacterial Activity ◽  
Lead Compound ◽  
Content Type ◽  
Tuberculosis Model

ABSTRACT Host-directed therapy in tuberculosis is a potential adjunct to antibiotic chemotherapy directed at Mycobacterium tuberculosis. Ambroxol, a lead compound, emerged from a screen for autophagy-inducing drugs. At clinically relevant doses, ambroxol induced autophagy in vitro and in vivo and promoted mycobacterial killing in macrophages. Ambroxol also potentiated rifampin activity in a murine tuberculosis model.

scholarly journals Secondary metabolites from Triclisia gilletii (De Wild) Staner (Menispermaceae) with antimycobacterial activity against Mycobacterium tuberculosis

2017 ◽  
Vol 33 (5) ◽  
pp. 642-650 ◽  
Author(s):  
Eric Robert Tiam ◽  
Dominique Serge Ngono Bikobo ◽  
Auguste Abouem A Zintchem ◽  
Norbert Mbabi Nyemeck ◽  
Esther Del Florence Moni Ndedi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Secondary Metabolites ◽  
Antimycobacterial Activity

scholarly journals The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4446-4452 ◽  
Author(s):  
Vadim Makarov ◽  
João Neres ◽  
Ruben C. Hartkoorn ◽  
Olga B. Ryabova ◽  
Elena Kazakova ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Nitro Group ◽  
Covalent Bond ◽  
Antimycobacterial Activity ◽  
Content Type ◽  
Sar Studies ◽  
Covalent Bond Formation

ABSTRACT8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1) and display nanomolar bactericidal activity againstMycobacterium tuberculosisin vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml againstM. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 μM and present favorablein vitroabsorption-distribution-metabolism-excretion/toxicity (ADME/T) andin vivopharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency.

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