Comparative evaluation of the 2-methyl-5-nitroimidazole compounds dimetridazole, metronidazole, secnidazole, ornidazole, tinidazole, carnidazole, and panidazole against Bacteroides fragilis and other bacteria of the Bacteroides fragilis group

Abstract

Tube-dilution MICs of seven 2-methyl-5-nitroimidazole compounds varying at the 1-substitution were determined against Bacteroides fragilis. Activities on a molar basis were ranked: tinidazole > panidazole > ornidazole > metronidazole 2 secnidazole > carnidazole > dimetridazole. Geometric mean MICs varied from 0.5 to 6.6 ,uM, and vulgatus, were within the range determined for B. fragilis.Increased awareness of anaerobic infections and the demonstration of the excellent activity of metronidazole against a wide range of obligately anaerobic bacteria (4-6, 18) have raised new medical interest in nitroimidazole drugs. Other derivatives have subsequently been found to be active against Bacteroides fragilis and considered not essentially different from metronidazole (2,3,9,12,20); there has seemed to be little reason to look for alternatives. However, significant differences exist between closely related 5-nitroimidazole compounds ( Fig. 1) with respect to pharmacokinetics (10,11,13,15,21,23,24), therapeutic results (13), and mutagenicity (1,17,25). Since such gradually accumulating information may cause reevaluations of the choice of drugs, we extended structure-activity investigations on the susceptibility of B. fragilis and report on a comparison of the seven 2-methyl-5-nitroimidazole derivatives which have reached clinical use (primarily in treating protozoal infections). MATERIALS AND METHODSBacteria. We studied B. fragilis ATCC 23745 (American Type Culture Collection, Rockville, Md.) and 33 other strains of B. fragilis originating from diagnostic clinical material. They had been isolated with enriched nonselective anaerobic blood agar and stored at -70°C in skim milk supplemented with 15% glycerol. Fourteen strains of B. distasonis, B. ovatus, B. thetaiotaomicron, B. uniformis, or B. vulgatus were similarly isolated and stored.Drugs. The chemistry of the compounds used appears in Table 1. Dimetridazole (batch P 0132-1) and metronidazole (batch 8222200) were gifts from Rhone-Poulenc Pharma Norden A/S, Birker0d, Denmark; secnidazole (RP 14539; lot 18) was from Rhone-Poulenc, Paris, France; ornidazole (Ro 7-0207) was from Hoffmann-La Roche Inc., Nutley, N.J.; tinidazole (lot 207 TZ 030) was from Pfizer Inc., New York, * Corresponding author. N.Y.; carnidazole (R 25831; batch A 8301) was from Janssen Pharmaceutica N.V., Beerse, Belgium; and panidazole (batch 4 RI/A) was from Ward Blenkinsop & Co. Ltd., Widnes, United Kingdom. Each was dissolved in sterile distilled water to a 10-mM concentration, except carnidazole (4 mM), and stored in 1-ml samples in the dark at -20°C. Each solution was sterilized with a 0.22-,um (pore size) filter (Optex for ophthalmic solutions; Millipore Corp., Bedford, Mass.) before use.Inoculum. All work with the bacteria took place at room temperature inside an anaerobic chamber (model 800 anaerobic environmental system; Capco, Sunnyvale, Calif.), and the cultures were incubated at 37°C in transfer modules (model 830; Capco). All media were prereduced for 24 h or longer before use and not e...

Nitroimidazoles for the Treatment of TB: Past, Present and Future

“…and ranked according to their activity: tinidazole (7) > panidazole (8) > ornidazole (9) > metronidazole ≥ secnidazole (10) > carnidazole (11) > dimetridazole (12 ; Table 2) [25]. Another 5-nitroimidazole GO-10213 (13) was found to be more active than metronidazole against aerobes, microaerophilic organisms and anaerobes but development halted due to the mutagenicity of the imidazolidinone ring [26].…”

Thermodynamic Scaling of the Dynamics of a Strongly Hydrogen-Bonded Glass-Former

“…In this contribution we characterize experimentally the molecular dynamics of the strongly hydrogen-bonded ternidazole drug (3-(2-methyl-5-nitroimidazol-1-yl)-propan-1-ol, C 7 H 11 N 3 O 3 , hereinafter TDZ) 16 , 17 in its amorphous state (supercooled liquid and glass). Hydrogen bonding in TDZ is so strong that the crystalline phase of TDZ consists of tetramers held together by intermolecular hydrogen bonds involving the oxygen moieties 18 .…”

Comparative activity of metronidazole and tinidazole against Clostridium difficile and Peptostreptococcus anaerobius

“…The family comprises numerous drugs, and over 10-fold differences in in vitro activity against Bacteroides fragilis have been reported, even if only the compounds used in human medicine are considered (19,25). Comparative studies have been largely confined to the model pathogen B. fragilis, which has been found to be more susceptible to tinidazole than to metronidazole (7,14,16,19,25,26). The same relationship between the two drugs has been found with Giardia lamblia in vitro (18) and in the treatment of giardiasis (17).…”