Structural investigations of mode of action of drugs. III. Structure of rifamycin S iminomethyl ether

Abstract

A structural study of rifamycin S iminomethyl ether (C38H47NO12) has been carried out by X-ray diffraction. The needle-shaped crystals belong to orthorhombic space group P212121. The unit-cell dimensions are a = 14.059 (3), b = 21.420 (5) and c = 26.961 (5) A. There are two molecules per asymmetric unit and eight molecules in the cell. The structure, with 102 nonhydrogen atoms in the asymmetric unit, was solved by repeated use of direct methods via tangent extension and refined by least-squares techniques to a final weighted residual of 0.109 for 4351 independent reflections. Attempts to locate H atoms were partially successful. The introduction of an extra double bond N=C(15) had a pronounced effect on the conformation of the ansa chain. The C(16)-C(17) and C(18)-C(19) double bonds are cis and trans respectively. The C(21)-O(10) and C(23)-O(9) bonds point toward the naphthoquinone ring rather than being parallel to it. A similar situation is observed in tolypomycinone and this seems to be the reason for the inactivity of both these compounds. There are four intramolecular and two intermolecular hydrogen bonds.

Structural, functional, and genetic analysis of sorangicin inhibition of bacterial RNA polymerase

“…Derivatives of Rif and their effects on antimicrobial activity have been analyzed extensively (Brufani et al , 1964; Lancini and Zanichelli, 1977; Arora, 1981, 1983, 1985; Arora and Main, 1984). Modifications of the ansa bridge, O1 or O2 of the napthol ring, or the hydroxyls O9 or O10 greatly reduce its inhibition activity in vitro .…”

“…This residue typifies the Class II mutants; substitutions of Ser(531/411) with bulky hydrophobic residues (Phe or Tyr) led to strong Rif resistance but mild or no Sor resistance (Table I). Substitution of this residue would remove a potentially important hydrogen bond with Rif‐O2 (Brufani et al , 1964; Lancini and Zanichelli, 1977; Arora, 1981, 1983, 1985; Arora and Main, 1984). Modeling indicates that substitution of Ser(531/411) with Phe or Tyr would also introduce a severe steric clash with the napthol rings of Rif.…”

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

“…The overall inclination of the ansa on the chromophore varies continuously from 64°to 124°for active rifamycins, while it can be less than 50°for nonactive compounds. 6,11,12 The amidic junction is planar (C1-C2-N-C15 ) 174.2(5)°and C2-N-C15-O11 (T1) ) 9.5 (5)°), and O11 is oriented on the opposite side of the C2-N bond with respect to O1. This arrangement favors the occurrence of two intramolecular hydrogen bonds: N-H‚‚‚O1 (N‚‚‚O1 ) 2.629(5) Å, N-H‚‚‚O1 ) 108(1)°) and C3-H‚‚‚O11 (C3‚‚‚O11 ) 2.855(6) Å, C3-H‚‚‚O11 ) 123(1)°).…”

Structure of 21-acetoxy-11(R)-rifamycinol S. The role of the one- and two-phase semi-invariants in multisolution phasing methods

“…Among the rifamycin derivatives, two inactive semi-synthetic compounds, rifamycin S iminomethyl ether (Arora, 1981) and cyclized rifamycin SV (Arora, 1984), have been studied in the solid state. The molecular structures show that the chemical modifications that they have undergone produce remarkable conformational changes and destroy the abovementioned three-dimensional requirements responsible for the biological activity.…”