Hydrogenation of the <i>ansa</i>‐Chain of Rifamycins. X‐ray crystal structure of (16<i>S</i>)‐16,17,18,19‐tetrahydrorifamycin S

Bartolucci, Cecilia; Cellai, Luciano; Filippo, Patrizia Di; Lamba, Doriano; Segre, Anna Laura; Bianco, A.; Guiso, Marcella; Pasquali, Vinicio; Brufani, M.

doi:10.1002/hlca.19930760406

Cited by 3 publications

(2 citation statements)

References 16 publications

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“…The use of objective methods to highlight the structural parameters which are relevant for rifamycin activity is further developed in the present work with the aim of obtaining a more accurate model adding one more observation to the 24 different molecular conformations found in 19 rifamycins so far characterized by X-ray diffraction. − Figure depicts the chemical diagrams of all the structurally known rifamycins. An unbiased description of the molecular conformation has been formulated by considering the 17 torsion angles along the ansa chain backbone, from T1 = C2−N−C15−C16 to T17 = C29−O5−C12−O3, the 6 interatomic distances between the 4 oxygens of the pharmacophore (D1 = O1···O2, D2 = O1···O9, D3 = O1···O10, D4 = O2···O9, D5 = O2···O10, D6 = O9···O10), and the 3 angles between the chromophore and the vector C21− O9 (A1), the chromophore and the vector C23−O10 (A2), and the chromophore and the ansa chain mean planes (A3), respectively.…”

Section: Resultsmentioning

confidence: 99%

“…The Cambridge Structural Database 32 was searched to retrieve structural data for all rifamycins characterized by X-ray diffraction. 11,12,[14][15][16][17][18][19][20][21][22] In some cases 6,16 coordinates were not deposited and were kindly provided by authors. To these (16 active, 9 nonactive), data concerning rifamycin O were added, for a total of 26 independent molecules.…”

Section: Methodsmentioning

confidence: 99%

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Comprehensive Study on Structure−Activity Relationships of Rifamycins: Discussion of Molecular and Crystal Structure and Spectroscopic and Thermochemical Properties of Rifamycin O

Bacchi¹,

Pelizzi²,

Nebuloni³

et al. 1998

J. Med. Chem.

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The mechanism of action of rifamycins against bacterial DNA-dependent RNA polymerase has been explained on the basis of the spatial arrangement of four oxygens which can form hydrogen bonds with the enzyme. Structural descriptors are derived from X-ray diffraction crystal structures of 25 active and nonactive rifamycins. Principal component analysis is used to find the combination of structural parameters which better discriminate between active and nonactive rifamycins. Two possible mechanisms of molecular rearrangement are described which can convert nonactive into active conformations. The energy involved for conformational rearrangements is studied by molecular modeling techniques. Methyl C34 is found to play a key role for determining the geometry of the pharmacophore. Rifamycin O, reported to be active, is obtained by oxidation of rifamycin B and is studied by X-ray single-crystal diffractometry, by solution IR and NMR spectroscopy, and by thermal analysis. Surprisingly the oxidation process is totally stereospecific, and an explanation is given based on solution spectroscopic evidence. The conformation found in the solid state is typical of nonactive compounds, and molecular mechanics calculations show that a molecular rearrangement to the active conformation would require about 15 kcal/mol. Thermal analysis confirms that rifamycin O has a sterically constrained conformation. Therefore, it is likely that the antibiotic activity of rifamycin O is due either to chemical modification prior to reaching the enzyme or to conformational activation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Comprehensive Study on Structure−Activity Relationships of Rifamycins: Discussion of Molecular and Crystal Structure and Spectroscopic and Thermochemical Properties of Rifamycin O

Bacchi¹,

Pelizzi²,

Nebuloni³

et al. 1998

J. Med. Chem.

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Rifamycins – Obstacles and opportunities

Aristoff¹,

et al. 2010

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Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules

Mosaei

Zenkin

2020

EcoSal Plus

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RNA polymerases (RNAPs) accomplish the first step of gene expression in all living organisms. However, the sequence divergence between bacterial and human RNAPs makes the bacterial RNAP a promising target for antibiotic development. The most clinically important and extensively studied class of antibiotics known to inhibit bacterial RNAP are the rifamycins. For example, rifamycins are a vital element of the current combination therapy for treatment of tuberculosis. Here, we provide an overview of the history of the discovery of rifamycins, their mechanisms of action, the mechanisms of bacterial resistance against them, and progress in their further development.

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Hydrogenation of the ansa‐Chain of Rifamycins. X‐ray crystal structure of (16S)‐16,17,18,19‐tetrahydrorifamycin S

Abstract: The catalytic hydrogenation of rifamycin S (2) over Pd/C, followed by oxidation with K, [Fe(CN) J, generates a pair of 16,17,18,19-tetrahydrorifamycins S (3/4), epimeric at C(16). The use of PtO, as catalyst leads to the hydrogenation also of the C(28)=C (29)

Cited by 3 publications

References 16 publications

Comprehensive Study on Structure−Activity Relationships of Rifamycins: Discussion of Molecular and Crystal Structure and Spectroscopic and Thermochemical Properties of Rifamycin O

Comprehensive Study on Structure−Activity Relationships of Rifamycins: Discussion of Molecular and Crystal Structure and Spectroscopic and Thermochemical Properties of Rifamycin O

Rifamycins – Obstacles and opportunities

Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules

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