Norikazu Matsuhashi

Antimycobacterial Activities of Novel Levofloxacin Analogues

ABSTRACT In order to investigate structure-activity relationships between antimycobacterial activities and basic substituents at the C-10 position of levofloxacin (LVFX), we synthesized a series of pyridobenzoxazine derivatives by replacement of theN-methylpiperazinyl group of LVFX with various basic substituents. A compound with a 3-aminopyrrolidinyl group had one-half the activity of LVFX against Mycobacterium avium, M. intracellulare, and M. tuberculosis. Mono- and dimethylation of the 3-amino moiety of the pyrrolidinyl group increased the activities against M. avium and M. intracellulare but not those against M. tuberculosis. On the other hand, dialkylation at the C-4 position of the 3-aminopyrrolidinyl group enhanced the activities against M. avium, M. intracellulare, and M. tuberculosis. Thus, introduction of an N-alkyl or aC-alkyl group(s) into the 3-aminopyrrolidinyl group may contribute to an increase in potency against M. avium,M. intracellulare, and/or M. tuberculosis, probably through elevation of the lipophilicity. However, among the compounds synthesized, compound VII, which was a 2,8-diazabicyclo[4.3.0]nonanyl derivative with relatively low lipophilicity, showed the most potent activity against mycobacterial species: the activity was 4- to 32-fold more potent than that of LVFX and two to four times as potent as that of gatifloxacin. These results suggested that an increase in the lipophilicity of LVFX analogues in part contributed to enhancement of antimycobacterial activities but that lipophilicity of the compound was not a critical factor affecting the potency.

Discovering small molecules that inhibit adipogenesis and promote osteoblastogenesis: Unique screening and Oncostatin M-like activity

Oncostatin M (OSM), one of the IL-6 family cytokines, inhibits adipogenic differentiation and stimulates osteoblastogenic differentiation from human bone marrow mesenchymal stem cells (hBMSCs). This functional study of OSM enabled us to develop a two-dimensional small-molecule screen that shifts hBMSC differentiation from adipocyte to osteoblast. Several structurally related compounds (isoxazoles) inhibited the accumulation of intracellular lipid droplets, whereas they promoted alkaline phosphatase activity and extracellular matrix calcification. Isoxazoles also reduced the expression of adipogenic transcription factor PPARγ and increased the levels of osteogenic transcription factors Runx2 and Osterix. They also induced the expression of the Wnt/β-catenin downstream gene and TOPflash reporter; however, the dephosphorylated β-catenin-active form was not significantly increased. Interestingly, the slight modification of the active compound led to a complete reversion of the dual differentiation activities. In summary, we have identified isoxazoles with anti-adipogenic and pro-osteogenic activities that provide a potential new tool for exploring the lineage commitment of mesenchymal stem cells and a possible lead for therapeutic intervention in osteopenia and osteoporosis.

Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria.

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.