In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins

Abstract

Newly synthesized rifamycin derivatives, KRM-1648, KRM-1657, KRM-1668, KRM-1686, and KRM-1687, having the chemical structures of 3'-hydroxy-5'-(4-alkylpiperazinyl)-benzoxazinorifamycins (alkyl residues: isobutyl, propyl, sec-butyl, sec-butyl [R configuration], and sec-butyl [S configuration], respectively), were studied for their in vitro antimycobacterial activities. Representative (KRM-1648) MICs for 90% of the strains tested, determined by the agar dilution method on 7H11 medium, of various pathogenic mycobacteria (9 species, 174 strains) were as follows (in micrograms per milliliter): Mycobacterium tuberculosis (rifampin [RMP]-susceptible strains), <0.0125; M. tuberculosis (RMP-resistant strains), 12.5; M. kansasii, 0.05; M. marinum, .0.0125; M. scrofulaceum, 0.1; M. avium, 1.56; M. intracellulare, 0.1; M. fortuitum, >100; and M. chelonae subsp. abscessus and M. chelonae subsp. chelonae, >100. These values are more than 64 times lower than those of RMP, except for the values against RMP-resistant M. tuberculosis (8 times lower) and those against rapid growers, including M. fortuitum and M. chelonae (the same as those of RMP). The other derivatives had similar levels of in vitro activity against these mycobacteria. When murine peritoneal macrophages in which M. intracellulare was phagocytosed in vitro were cultured in the presence of the benzoxazinorifamycins (1 ,ug/ml), much more rapid killing of the organisms ingested in the macrophages was seen compared with when the same amount of RMP was added to the medium. The addition of benzoxazinorifamycins at the concentration of 0.05 ,ig/ml caused more marked suppression of intracellular growth of the organisms compared with addition of RMP. KRM-1648 and KRM-1657 inhibited intracellular growth of M. tuberculosis, and their efficacies were much greater than that of RMP.Rifampin (RMP), a rifamycin derivative, is highly active against a number of mycobacteria, especially slow growers such as Mycobacterium tuberculosis, M. kansasii, and M. marinum (3,22,23), and is used for the treatment of patients with tuberculosis and some atypical mycobacterial infections (4,8,17,21,27 (4,21,27) because of its considerably weak in vitro activity against the MAC (3, 22, 23), possibly because of the permeability barrier of the organisms (7,20). Although other types of rifamycin derivatives, e.g., rifabutin (RBT) (2), rifapentine (1), FCE22807 (6), CGP40/469A (6), CGP-7040 (10), and P-DEA (10), have been developed and although the drugs have higher in vitro antimycobacterial activities than RMP (2, 3, 5, 9, 23, 28), the drugs are generally not so active against MAC infection in humans, particularly immunocompromised hosts (12,14,29). Since MAC infections are increasing remarkably in immunocompromised hosts, particularly in AIDS patients (30), the need to develop new antimicrobial agents including rifamycin derivatives which have a strong activity against the MAC is urgent. In this study, we described the in vitro activities of newly synthesized benzoxazinorifamycins against various p...

In vitro antimicrobial activity of benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex, determined by the radiometric method

“…However, the newly developed BACTEC 460 TB system (3,5,9) has made it possible to determine drug susceptibility within 1 week (6,8,10,13). Previously, 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin (KRM-1648; KANEKA Corporation, Hyogo, Japan) demonstrated excellent in vitro activity against slowly growing mycobacteria, especially Mycobacterium avium complex (MAC), in our experiment to determine its MICs for various mycobacterial strains by the agar dilution method using Middlebrook 7H11 agar plates (7). KRM-1648 also exhibited excellent therapeutic efficacy against MAC infections induced in BALB/c and NK-deficient beige mice (12) and in rabbits (unpublished observation) and also demonstrated potent therapeutic activity against M. marinum infection induced in BALB/c mice (14).…”

Synthesis of azatricyclodiones & octahydro-benzo[f]isoindoles and their antimicrobial evaluation

“…Compounds 3,5,7,9, were obtained exclusively when two equivalents of furfuryl amines were reacted separately with 1a -1d. Compounds 11, and 12 were similarly prepared from maleimides 1f and 1 g. (2) ,4,4a,5,8,8a,9, 4,4,4a,5,8,8a,9, ,4,4a,5,8,8a,9, General method of preparation of compounds (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) …”

“…All the compounds synthesized were evaluated against Mycobacterium tuberculosis H37Ra [21] and Mycobacterium tuberculosis Rv strains [22], Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus strains of bacteria and Candida albicans, Cryptococcus neoformans, Sporothrix schenckii, Trichophyton mentagrophytes, Aspergillus fumigatus, Candida parapsilosis (ATCC-22019) strains of fungi [23 -26]. Antibacterial and antifungal screening results are shown in Table I.…”

Is It Easy to Stop RNA Polymerase?

“…11 Moreover, a wealth of information yielded by combinatorial chemistry failed to produce any robust rules for rifamycin design. The latest Rif compound that was hailed as a new "wonder drug," rifalazil, 12 exhibited severe side-effects in clinical trials and was abandoned. 13 Thus, in spite of numerous efforts, the classic combinatorial approach failed to produce the "perfect" Rif, underscoring the urgent need for unraveling the molecular mechanisms of Rif action and the bacterial resistance to these drugs at the atomic level.…”