Assessment of carbapenems in a mouse model of Mycobacterium tuberculosis infection.

We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.

Imidazole and 1,2,4-Triazole-based Derivatives Gifted with Antitubercular Activity: Cytotoxicity and Computational Assessment.

BACKGROUND: Mycobacterium Tuberculosis (Mtb) is the causative pathogen of Tuberculosis (TB) and outbreaks are more common among immunosuppressed persons infected with HIV. The current treatment regimens are lengthy and toxic, yet the therapy has remained unchanged for many decades, so there is a need to find new structures with selective mechanism of action. Moreover, the increased incidence of severe disseminated infections produced by undiagnosed Multidrug-resistant (MDR), worsen clinical treatment and contribute the spread of the disease. OBJECTIVE: The aim of our study was to evaluate the potential of imidazole and triazole moieties for antimycobacterial activity, by synthesizing some 1-(1-(aryl)-2-(2,6-dichlorophenyl)hydrazono)ethyl- 1H-imidazole and 1H-1,2,4-triazole derivatives 2a-l. METHODS: The title compounds were obtained via classical organic synthesis. The antimicrobial activity was evaluated using the method of microdilution and the cytotoxicity assay was performed by MTT method. RESULTS: The results indicated that the presence of both the imidazole ring and that of the 2,6- dichlorosubstituted phenyl moiety, is more relevant for inhibitory activity against Mtb than the triazole nucleus and the unsubstituted phenyl ring. Among the series, (E)-1-(2-(5-chlorothiophen-2-yl)-2-(2- (2,6-dichlorophenyl)hydrazono)ethyl)-1H-imidazole derivative 2f and (Z)-1-(2-([1,1'-biphenyl]-4-yl)- 2-(2-(2,6-dichlorophenyl)hydrazono)ethyl]-1H-imidazole derivatives 2e exhibited a promising antimycobacterial property and the latter also displayed a safe cytotoxic profile. CONCLUSION: The synthesized compounds were studied for their antitubercular activity. Among the series, the compounds 2e and 2f appeared to be the most promising agents and, according to the docking assessment, the compounds could be CYP51 inhibitors. These evidences could be useful for the future development of new antimycobacterial derivatives targeting CYP51 with more specificity for the mycobacterial cell enzyme.

Facile synthesis of 1,3-thiazolidin-4-ones as antitubercular agents.

We have developed, highly efficient, one-pot, solvent-free, [Et3NH][HSO4] catalyzed multicomponent reaction protocol for the synthesis of 1,3-thiazolidin-4-ones in excellent yields. For the first time, the 1,3-thiazolidin-4-ones were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis dormant MTB H37Ra and Mycobacterium bovis BCG strains. Among the synthesized basic 1,3-thiazolidin-4-ones, particularly the compounds 4c, 4d, 4e, 4f, 4h, 4i and 4j displays promising antitubercular activity along with no significant cytotoxicity against the cell lines MCF-7, A549 and HCT-116.

Computational Sampling and Simulation Based Assessment of Novel Mycobacterium tuberculosis Glutamine Synthetase Inhibitors: Study Involving Structure Based Drug Design and Free Energy Perturbation.

The highly persistent nature of Mycobacterium tuberculosis can be attributed to its lipophilic cell wall which acts as a major barrier in the process of drug discovery against tuberculosis. Glutamine synthetase plays a major role in nitrogen metabolism and cell wall biosynthesis of pathogenic mycobacteria. The current review focuses on the structural and functional aspects of Mtb glutamine synthetase and an overview of its reported inhibitors till date. Also in the present study, we employed a computational structure based drug design protocol for identifying novel inhibitors against Mtb glutamine synthetase (MtbGS). A total of 12 hits were identified based on e-pharmacophore related search and virtual screening, which were further tested for their in vitro MtbGS inhibitory activity. Three compounds (compound 6, 1 and 12) were found with IC50 less than 5 µM, of which compound 6 being top active with IC50 of 2.124 µM. Differential scanning fluorimetry studies were employed so as to measure the thermal stability of the protein complexed with the most active compound. Also the protein complexes with top three active compounds were subjected for molecular dynamics simulations to study their binding pattern and stabilization effect. The solvation free energies were also determined for these compounds, undertaking free energy perturbation studies, which can be used further for lead optimization in the process of anti-tubercular drug discovery targeting Mtb glutamine synthetase.

Efficient Synthesis and Anti-Tubercular Activity of a Series of Spirocycles: An Exercise in Open Science.

Tuberculosis afflicts an estimated 2 billion people worldwide and causes 1.3 million deaths annually. Chemotherapeutic solutions rely on drugs developed many years ago, with only one new therapeutic having been approved in the last 40 years. Given the rise of drug-resistant strains, there is an urgent need for the development of a more robust drug development pipeline. GlaxoSmithKline recently placed the structures and activities of 177 novel anti-tubercular leads in the public domain, as well as the results of ongoing optimisation of some of the series. Since many of the compounds arose from screening campaigns, their provenance was unclear and synthetic routes were in many cases not reported. Here we present the efficient synthesis of several novel analogues of one family of the GSK compounds-termed "Spiros"-using an oxa-Pictet-Spengler reaction. The new compounds are attractive from a medicinal chemistry standpoint and some were potent against the virulent strain, suggesting this class is worthy of further study. The research was carried out using open source methodology, providing the community with full access to all raw experimental data in real time.

An efficient one pot syntheses of aryl-3,3'-bis(indolyl)methanes and studies on their spectral characteristics, DPPH radical scavenging-, antimicrobial-, cytotoxicity-, and antituberculosis activity.

An efficient one-pot syntheses of aryl-3,3'-bis(indolyl)methanes (BIMs) from indole/2-methylindole and formylphenoxyaliphatic acid(s) is described. Esterification of carboxylic acid and aromatic electrophilic substitution reactions are achieved simultaneous in the presence of potash alum as a catalyst. This catalyst could be recovered and reused without substantial loss in its catalytic activity and the methodology could be applied on a range of closely related substrates. The solvation characteristics in ground and excited states of the compounds by monitoring the absorbance and fluorescence band maxima have been studied. The fluorescence studies in protic and aprotic solvents were rationalized on the basis of solute-solvent interaction and substituents effect on these photophysical processes analyzed. The compounds prepared showed efficient antimicrobial effect against human pathogens, cytotoxicity against A431 cell line, and DPPH radical scavenging effect. Single crystal XRD studies have been carried out for a few compounds synthesized in this work.

A highly atom economic, chemo-, regio- and stereoselective synthesis and evaluation of spiro-pyrrolothiazoles as antitubercular agents.

The 1,3-dipolar cycloaddition of azomethine ylides derived from substituted isatins and 1,3-thiazolane-4-carboxylic acid to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones afforded novel spiro-pyrrolothiazoles chemo-, regio- and stereoselectively in quantitative yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB) using agar dilution method. Among the synthesized compounds, spiro[5.3'']-5''-nitrooxindole-spiro-[6.3']-1'-methyl-5'-(2,4-di-chlorophenylmethylidene)tetrahydro-4'(1H)-pyridinone-7-(2,4-dichlorophenyl)tetra-hydro-1H-pyrrolo[1,2-c][1,3]thiazole (9k) was found to be the most active with a minimum inhibitory concentration (MIC) of 0.6microM against MTB and MDR-TB.

An atom economic synthesis and antitubercular evaluation of novel spiro-cyclohexanones.

The 1,3-dipolar cycloaddition of azomethine ylides derived from acenaphthenequinone and alpha-amino acids viz. sarcosine, phenylglycine, 1,3-thiazolane-4-carboxylic acid and proline to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded novel spiro-heterocycles chemo-, regio- and stereoselectively in quantitative yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Two compounds, 4-(2,4-dichlorophenyl)-5-phenylpyrrolo(spiro[2.2'']acenaphthene-1''-one)spiro[3.2']-6'-(2,4-dichlorophenylmethylidene)cyclohexanone (4i) and spiro[5.2'']acenaphthene-1''-onespiro[6.2']-6'-(2,4-dichlorophenylmethylidene)cyclohexanone-7-(2,4-dichlorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole (5i) display maximum activity in vitro with a MIC value of 0.40microg/mL against MTB and were 4 and 15.6 times more potent than ethambutol and pyrazinamide, respectively.

Discovery of antimycobacterial spiro-piperidin-4-ones: an atom economic, stereoselective synthesis, and biological intervention.

An atom economic and stereoselective synthesis of several spiro-piperidin-4-ones through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin and alpha-amino acids viz . proline, phenylglycine, and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones is described. These compounds were evaluated for their in vitro and in vivo activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)). Compound 4-(4-fluorophenyl)-5-phenylpyrrolo(spiro[2.3'']oxindole)spiro[3.3']-1'-methyl-5'-(4-fluorophenylmethylidene)piperidin-4'-one (4e) was found to be the most active in vitro with a MIC value of 0.07 microM against MTB and was 5.1 and 67.2 times more potent than isoniazid and ciprofloxacin, respectively. In vivo, compound 4e decreased the bacterial load in lung and spleen tissues with 1.30 and 3.73-log 10 protections respectively and was considered to be promising in reducing bacterial count in lung and spleen tissues.