Synthesis and evaluation of rifabutin analogs against Mycobacterium avium and H37Rv, MDR and NRP Mycobacterium tuberculosis

Figueiredo, Ricardo G.; Moiteiro, Cristina; Medeiros, M. A.; Silva, P. Almeida da; Ramos, Daniela Fernandes; Spies, Fernanda Sá; Ribeiro, Marta Osório; Lourenço, Maria Cristina S.; Júnior, I Neves; Gaspar, Maria Manuela; Cruz, M.E.M.; Curto, Manuel; Franzblau, Scott G.; Orozco, Héctor; Aguilar, Diana; Hernández-Pando, Rogelio; Costa, María do Céu

doi:10.1016/j.bmc.2008.12.006

Cited by 27 publications

(28 citation statements)

References 18 publications

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“…For this reason, the treatment of Tb is associated to a multidrug combination therapy for at least 6 months [1]. Therefore, to improve the therapeutic compliance, new and more effective drugs are urgently needed [1,5], requiring their development new approaches to understand the mechanism of action of classical therapies.…”

Section: Introductionmentioning

confidence: 99%

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Pinheiro

Giner‐Casares

Lúcio

et al. 2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

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This work focuses on the interaction of mycolic acids (MAs) and two antimycobacterial compounds (Rifabutin and N'-acetyl-Rifabutin) at the pulmonary membrane level to convey a biophysical perspective of their role in disease. For this purpose, accurate biophysical techniques (Langmuir isotherms, Brewster angle microscopy, and polarization-modulation infrared reflection spectroscopy) and lipid model systems were used to mimic biomembranes: MAs mimic bacterial lipids of the Mycobacterium tuberculosis (MTb) membrane, whereas Curosurf® was used as the human pulmonary surfactant (PS) membrane model. The results obtained show that high quantities of MAs are responsible for significant changes on PS biophysical properties. At the dynamic inspiratory surface tension, high amounts of MAs decrease the order of the lipid monolayer, which appears to be a concentration dependent effect. These results suggest that the amount of MAs might play a critical role in the initial access of the bacteria to their targets. Both molecules also interact with the PS monolayer at the dynamic inspiratory surface. However, in the presence of higher amounts of MAs, both compounds improve the phospholipid packing and, therefore, the order of the lipid surfactant monolayer. In summary, this work discloses the putative protective effects of antimycobacterial compounds against the MAs induced biophysical impairment of PS lipid monolayers. These protective effects are most of the times overlooked, but can constitute an additional therapeutic value in the treatment of pulmonary tuberculosis (Tb) and may provide significant insights for the design of new and more efficient anti-Tb drugs based on their behavior as membrane ordering agents.

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Section: Introductionmentioning

confidence: 99%

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Pinheiro

Giner‐Casares

Lúcio

et al. 2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…RFB was isolated from Mycobutin and further purified as previously described. [8] RFB2 was obtained from RFB by selective acylation of the secondary amino group, as previously described. [8] RFB3 was also synthesized from RFB, as described below.…”

Section: Methodsmentioning

confidence: 99%

“…[8] RFB2 was obtained from RFB by selective acylation of the secondary amino group, as previously described. [8] RFB3 was also synthesized from RFB, as described below. Sodium chloride, monopotassium phosphate, and dipotassium phosphate (99 % pure) were purchased from Panreac.…”

Section: Methodsmentioning

confidence: 99%

“…In comparison to RFB, RFB2 has an extra acetyl group, has shown better in vitro and in vivo therapeutic indices, and is thus a promising drug for clinical application in TB treatment. [8] RFB3 bears a bulkier butanoyl group (COC 3 H 7 ), which was added with the major goal of improving the pharmacokinetic properties as an anti-TB drug candidate. In addition, the partition coefficient log P predicted for RFB by using MarvinView 5.11.5 from Chemaxon was 4.53.…”

Section: Introductionmentioning

confidence: 99%

“…[6,7] In this context, N'-acetyl-rifabutin (RFB2, Figure 1) was obtained from RFB by selective acylation of the secondary amino group, as previously described. [8] In addition, N'-butanoyl-rifabutin (RFB3, Figure 1) was obtained from RFB as described in the Experimental Section. In comparison to RFB, RFB2 has an extra acetyl group, has shown better in vitro and in vivo therapeutic indices, and is thus a promising drug for clinical application in TB treatment.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the Structure–Activity Relationship of Rifabutin and Analogs: A Drug–Membrane Study

et al. 2013

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This work focuses on the influence of rifabutin and two novel analogs, namely, N'-acetyl-rifabutin and N'-butanoyl-rifabutin, on the biophysical properties of lipid membranes. Monolayers and multilamellar vesicles composed of egg L-α-phosphatidylcholine:cholesterol in a molar ratio of 4:1 are chosen to mimic biological membranes. Several accurate biophysical techniques are used to establish a putative relationship between the chemical structure of the antimycobacterial compounds and their activity on the membranes. A combination of in situ experimental techniques, such as Langmuir isotherms, Brewster angle microscopy, polarization-modulated infrared reflection-absorption spectroscopy, and small-angle X-ray scattering, is used to assess the drug-membrane interaction. A relationship between the effect of a drug on the organization of the membranes and their chemical structure is found and may be useful in the development of new drugs with higher efficacy and fewer toxic effects.

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Natural and Nature‐Inspired Macrocycles

Wessjohann

Bartelt

Brandt

2017

Practical Medicinal Chemistry With Macrocycles

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Synthesis and evaluation of rifabutin analogs against Mycobacterium avium and H37Rv, MDR and NRP Mycobacterium tuberculosis

Cited by 27 publications

References 18 publications

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Evaluation of the Structure–Activity Relationship of Rifabutin and Analogs: A Drug–Membrane Study

Natural and Nature‐Inspired Macrocycles

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