Potential Antituberculosis Agents Research Articles

Quinoxaline 1,4-di-N-Oxide and the Potential for Treating Tuberculosis

New drugs active against drug-resistant tuberculosis are urgently needed to extend the range of TB treatment options to cover drug resistant infections. Quinoxaline derivatives show very interesting biological properties (antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal) and evaluation of their medicinal chemistry is still in progress. In this review we report the properties and the recent developments of quinoxaline 1,4-di-N-oxide derivatives as potential anti-tuberculosis agents. Specific agents are reviewed that have excellent antitubercular drug properties, are active on drug resistant strains and non-replicating mycobacteria. The properties of select analogs that have in vivo activity in the low dose aerosol infection model in mice will be reviewed.

A new route to indoles via in situ desilylation–Sonogashira strategy: identification of novel small molecules as potential anti-tuberculosis agents

A new Pd/C-mediated tandem reaction has been developed for the one pot synthesis of indoles containing an o-(RSO2NH)C6H4 group at the C-2 position. The methodology provided novel indoles as inhibitors of Mycobacterium tuberculosis H37Rv chorismate mutasein vitro representing the first example of chorismate mutase inhibition by a heteroarene based small molecule.

A new class of potential anti-tuberculosis agents: Synthesis and preliminary evaluation of novel acrylic acid ethyl ester derivatives

Novel acrylic acid ethyl ester derivatives were synthesized and evaluated as potential agents against Mycobacterium species. A versatile and efficient copper-catalyzed coupling process was developed and used to prepare a library of substituted acrylic acid ethyl ester analogs. Minimum inhibitory concentration assays indicated that two of these compounds 3 and 4 have greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Moreover, members of this new class of compounds appear to exhibit a specific anti-mycobacterial effect and do not inhibit the growth of the other Gram-positive or Gram-negative species tested.

Molecular Modeling of Mycobacterium Tuberculosis DNA Gyrase and its Molecular Docking Study with Gatifloxacin Inhibitors

Mycobacterium tuberculosis (Mt) is a leading cause of infectious disease in the world today. This outlook is aggravated by a growing number of Mt infections in individuals who are immunocompromised as a result of HIV infections. Thus, new and more potent anti-tuberculosis agents are necessary. Therefore, DNA gyrase was selected as a target enzyme to combat Mt. In this work, the first three-dimensional molecular model of the hypothetical structures for the Mycobacterium tuberculosis DNA gyrase (mtDNAg) was elucidated by a homology modeling method. In addition, the orientations and binding affinities of some gatifloxacin analogs with those new structures were investigated. Our findings could be helpful for the design of new more potent gatifloxacin analogs.

3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents

Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r(2) ranging from 0.83 to 0.92 and q(2) from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.

ChemInform Abstract: Pentacyclo‐undecane Derived Cyclic Tetra‐amines: Synthesis and Evaluation as Potent Antituberculosis Agents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Comparative QSAR studies of nitrofuranyl amide derivatives using theoretical structural properties

The global increase in multidrug-resistant Mycobacterium tuberculosis strains and intolerance of first-line anti-tuberculosis drugs may cause major health problems and necessitate modification of the structural therapy regimen. In an ongoing effort to develop new and potent anti-tuberculosis agents, a series of nitrofuranyl amides were subjected to quantitative structure–activity relationship (QSAR) analysis using various feature selection methods. Nitrofuranyl amide derivatives with good therapeutic indices are known to inhibit an enzyme responsible for bacterial cell-wall synthesis and act as novel mycobacterial inhibitors. Successful implementation of a predictive QSAR model largely depends on the selection of a preferred set of molecular descriptors that can signify the chemical–biological interaction. Genetic algorithm (GA), simulated annealing and stepwise regression are applied as variable selection methods for an effective comparison and model development. The results of two-dimensional QSAR showed that a combination of topological indices, hydrophobic properties and autocorrelation descriptors of different atomic properties could be explored to design potent anti-tubercular inhibitors. Further analysis using three-dimensional QSAR technique identifies a suitable model obtained by GA-partial least square method leading to anti-tubercular activity prediction. The influences of steric and electrostatic field effects generated by the contribution plot are analysed and discussed. Both two- and three-dimensional QSAR analyses of such derivatives provide important structural insights for designing potent anti-tuberculosis drugs.

Pentacyclo-undecane derived cyclic tetra-amines: Synthesis and evaluation as potent anti-tuberculosis agents

As part of an ongoing effort to develop highly potent anti-tuberculosis agents, fourteen pentacyclo-undecane (PCU) tetra-amine compounds were synthesized and screened for their in vitro anti- mycobacterial activity against two TB strains, H37Rv and XDR 194 [an extensively drug-resistant strain of tuberculosis]. Using the broth macrodilution method, nitrofuranylamide based compounds ( 6a and 6b) showed almost similar activities against the H37Rv strain of Mycobacterium tuberculosis when compared with the control drug, ethambutol. N-Geranyl piperazine PCU ( 8a) and trans– trans farnesyl piperazine PCU ( 8b) were 3.2 and 3.7 times more potent than commercially available ethambutol. Both isoprenyl PCU tetra-amine derivatives and N-decyl piperazine PCU ( 9a) were highly active against the XDR 194 strain of tuberculosis with MICs in the range of 0.63–3.02 μM. Cytotoxicities (IC 50) of isoprenyl based compounds ( 8a, 8b) and compound 9a were tested on a mammalian cell line [MDBK (Madin Darby bovine kidney epithelium)] with values of 30, 24 and 25 μM respectively.

3-Substituted Anilines as Scaffolds for the Construction of Glutamine Synthetase and DXP-Reductoisomerase Inhibitors

Access to a series of truncated ATP analogs, as potential anti-tuberculosis agents, has been explored via alkylation and acylation of 3-aminophenol, whereas chloroacetylation, using chloroacetyl chloride, and subsequent Arbuzov phosphonation of a series of 3-substituted anilines have afforded a series of phosphonate derivatives as potential antimalarial agents.

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 micromol/L, most often 4 to 32 micromol/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.

Structure-based design, synthesis of novel inhibitors of Mycobacterium tuberculosis FabH as potential anti-tuberculosis agents

Mycobacterium tuberculosis FabH, an essential enzyme in mycolic acids biosynthetic pathway, is an attractive target for novel anti-tuberculosis agents. Structure-based design, synthesis of novel inhibitors of mtFabH was reported in this paper. A novel scaffold structure was designed, and 12 candidate compounds that displayed favorable binding with the active site were identified and synthesized.

Synthesis and NMR elucidation of novel penta‐cycloundecane amine derivatives as potential antituberculosis agents

The synthesis and NMR elucidation of five novel penta-cycloundecane amine derivatives are reported. These compounds are potential antituberculosis agents. The (1)H and (13)C spectra showed major overlapping of methine signals of the cage skeleton making it extremely difficult to elucidate these compounds. The overlapping occurs as a result of the additions made to the carbonyl carbon (C-8/C-11) of the cage. The two-dimensional NMR technique proved to be a useful tool in overcoming this problem. All compounds reported are meso compounds thereby not only simplifying the NMR structure elucidation, but also making it indeed possible.

Synthesis and NMR elucidation of pentacyclo-undecane diamine derivatives as potential anti-tuberculosis drugs

The complete structural elucidation of six novel pentacycloundecane (PCU) derivatives is reported. The target molecules are potential anti-tuberculosis agents. The addition of side arms to the PCU cage skeleton at position C-8/C-11 results in major overlapping of the methine resonances of the 1H NMR spectrum. The use of 2D NMR techniques proved to be a very useful tool in overcoming the difficulties encountered in the elucidation of cage compounds using 1H and 13C spectra only. All compounds reported are meso compounds thereby simplifying the complexity of the NMR spectra.

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.

2-(Tricyclo[3.3.1.13,7]dec-2-ylamino)ethanol hemihydrate

The title adamantane derivative, C12H21NO·0.5H2O, was synthesized as part of an investigation into the biological activities of cage amino–alcohol compounds as potential anti-tuberculosis agents. The structure displays inter­molecular O—H⋯N, N—H⋯O, O—H⋯O hydrogen bonding and a layered packing structure with distinct hydro­philic and hydro­phobic regions. The water molecule lies on a twofold rotation axis.

Structure–activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents

Systematic structure–activity relationship studies of caprazamycin (CPZ) analogs, including the aminoribose-truncated 5 and the uridine-truncated 6, have been carried out. Both 5 and 6 were synthesized efficiently via diazepanone ring construction by intramolecular reductive alkylation of aminoaldehyde derivatives. The antibacterial activity of a range of analogs, including 5 and 6, against Mycobacteriumosis was evaluated, and it was found that the uridine, the aminoribose, and the fatty acyl side chains are crucial for antibacterial activity. This study would be a guide for designing novel anti-tuberculosis agents based on the 6′- N-alkyl-5′-β- O-aminoribosyl-glycyluridine class of antibiotics including the CPZs.

Screening for antimycobacterial activity of plants used in traditional medicine

Tuberculosis is a disease mainly caused by Mycobacterium tuberculosis. It is estimated that one-third of the world's population is infected with tuberculosis bacillus and two million people will develop an active disease per year. The increasing prevalence of the disease is due to the emergence of multidrug-resistant strains as well to the HIV pandemic which provides a large reservoir of highly susceptible individuals [1]. Since no anti-tuberculosis drugs have been introduced in the past 30 years, there is an urgent need for new effective anti-mycobacterial agents to circumvent new drug resistance cases. In this instance, the plant kingdom is undoubtedly a valuable source for new potential anti-tuberculosis agents to be explored [2].

Synthesis and Antituberculosis Activity of a Novel Series of Optically Active 6-Nitro-2,3-dihydroimidazo[2,1-b]oxazoles

In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv (MIC = 0.006 microg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships of these new compounds are presented.

Syntheses and studies of quinolone-cephalosporins as potential anti-tuberculosis agents

The syntheses and anti-tuberculosis activity of quinolone-cephalosporin conjugates ( 1 and 2) are described. Both showed broad-spectrum antibacterial activity and significant anti-TB activity. The carbamate-linked quinolone-cephem 2 showed better antimycobacterial activity, including anti-TB activity, than the direct amine-linked quinolone-cephem 1, while quinolone-cephem 1 was slightly more effective against some Gram-negative bacterial strains.

Design, Synthesis, and SAR Studies of Mefloquine‐Based Ligands as Potential Antituberculosis Agents

Design, Synthesis, and SAR Studies of Mefloquine‐Based Ligands as Potential Antituberculosis Agents