Biflavonoids as novel antituberculosis agents

A series of naturally occurring and synthetic biflavonoids was evaluated for inhibitory activity against Mycobacterium tuberculosis H37Rv (Mtb). Compounds 6, 24, and 25 demonstrated 96, 95, and 87% inhibition, respectively, at a screening concentration of 12.5 microg/mL. The type of linkage and the presence of methoxy- and nitro-substituents in biflavonoids may contribute to the observed inhibitory activity. The results of this study represent the discovery of biflavonoids as a potential new class of antituberculosis agent.     

Anilinopyrimidines as novel antituberculosis agents

A selection of novel anilinopyrimidine analogues have been found to have micromolar activity against Mycobacterium tuberculosis. This could potentially generate new lead compounds in the fight against multi-drug resistant tuberculosis.     

Search of chemical scaffolds for novel antituberculosis agents

A method to identify chemical scaffolds potentially active against Mycobacterium tuberculosis is presented. The molecular features of a set of structurally heterogeneous antituberculosis drugs were coded by means of structural invariants. Three techniques were used to obtain equations able to model the antituberculosis activity: linear discriminant analysis, multilinear regression, and shrinkage estimation-ridge regression. The model obtained was statistically validated through leave-n-out test, and an external set and was applied to a database for the search of new active agents. The selected compounds were assayed in vitro, and among those identified as active stand reserpine, N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), trifluoperazine, pentamidine, and 2-methyl-4,6-dinitro-phenol (DNOC). They show activity comparable to or superior to ethambutol, used in combination with other drugs for the prevention and treatment of Mycobacterium avium complex and drug-resistant tuberculosis.     

Chiral hplc-cd studies of the antituberculosis drug (+)-ethambutol

Long standing errors in major pharmacopoeiae (BP,USP, and Eu.Ph.) concerning the absolute stereochemistry of the widely used antituberculosis drug (+)-ethambutol have been clarified by unambiguous synthesis and chiral HPLC. on a Pirkle, covalent D -phenylglycine column of perbenzoyl derivatives of each stereomer; the enantiomeric (?)-(R,R) and (+)-(S,S)-ethambutols together with the optically inactive (meso)-(R,S)-ethambutol. This paper describes how circular dichroism (CD) alone and combined with HPLC is used to demonstrate this chiral separation and also to confirm the absolute stereochemistry of each stereomer of ethambutol and its synthetic precursor 2-aminobutan-1-ol from studies of ?exciton coupling.”? The strengths and weaknesses of these chiral techniques are discussed.     

Synthesis and antituberculosis activity of new fatty acid amides

This work reports the synthesis of new fatty acid amides from C16:0, 18:0, 18:1, 18:1 (OH), and 18:2 fatty acids families with cyclic and acyclic amines and demonstrate for the first time the activity of these compounds as antituberculosis agents against Mycobacterium tuberculosis H₃₇Rv, M. tuberculosis rifampicin resistance (ATCC 35338), and M. tuberculosis isoniazid resistance (ATCC 35822). The fatty acid amides derivate from ricinoleic acid were the most potent one among a series of tested compounds, with a MIC 6.25 μg/mL for resistance strains.     

An assessment of antituberculosis therapy in two animal models

The protective effects of ciprofloxacin and rufloxacin were compared to those of rifampicin againstMycobacterium tuberculosis infections in mice and in guinea pigs. Rifampicin was very protective in both models. In tubercular infections produced in mice, ciprofloxacin (30 mg/kg) showed slight protection but none was observed in guinea pigs. Rufloxacin, was weakly active in guinea pigs but inactive in mice.     

Novel and revisited approaches in antituberculosis drug discovery

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Image source (SEM of Mtb): NIAID.     

Diaryloxy methano phenanthrenes: a new class of antituberculosis agents

A new series of diaryloxy methano phenanthrenes were prepared through tertiary-aminoalkylations of [(methoxy-phenyl)-phenanthren-9-yl-methyl]-phenols obtained from Friedel-Crafts alkylations on (methoxy-phenyl)-phenanthren-9-yl-methanols. These series of compounds were evaluated against Mycobacterium tuberculosis H37Rv and showed the desired activity in the range of 6.25 microg/mL in vitro. One of the compound 12j protects the mice from the challenge of M. tuberculosis in vivo, as 30% of the mice were survived at treatment of 50 mg/kg body weight.     

The synthesis and antituberculosis activity of 5-alkynyl uracil derivatives

A series of new 5-alkynyl-substituted uracil and uridine derivatives were synthesised via palladium-catalysed Sonogashira cross-coupling reaction of 5-bromo-pyrimidine base with terminal acetylenes with good yields in DMF at room temperature. All obtained compounds were tested for antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis (H37Ra) at concentrations of 1–100 µg/ml using MABA test. Obtained results revealed that most of tested uracil derivatives exhibited high antimycobacterial activity (MIC₅₀ = 1.1–19.2 µg/ml) in comparison with therapeutic agents such as rifampicin, isoniazid and d-cycloserine, excluding compounds having alkyl substituent at triple alkyne bond.     

Synthesis of novel [1,2]-diamines with antituberculosis activity

Guided by the metabolism information of SQ109, derivatives with substituted geranylamine moiety or substituted admantane ring of SQ109 were synthesized and evaluated as antituberculosis agents. Among all tested compounds, compound 11c showed the most potent antituberculosis activity with MIC value of 0.3 μM against Mycobacterium tuberculosis H37Rv.     

Late toxicoses of pregnancy and transplacental transmission of antituberculosis antibodies]

The content of antituberculosis antibodies in the blood of neonates was studied with the aid of passive hemagglutination test (PHT) after Boiden and in the PHT modified after Middlebrook-Dubot. The use of a complex antigen from the BCG vaccine in the PHT proved to possess the greatest prospects; antituberculosis humoral antibodies were detected at the time of birth in 48.5% of the children. A total of 322 neonates, including 167 neonates born of mothers with late toxemia of pregnancy, were examined. With the given complication of pregnancy there was revealed a disturbance of the transplacental transmission of antituberculosis antibodies, this being explaining by the destructive-sclerotic changes in the placental tissue in marked toxemia of pregnancy.