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ABSTRACT
There is an essential need for searching for the new compounds effective in the treatment of infections caused E\PXOWLGUXJUHVLVWDQWEDFWHULD7KLVSDSHULVWKHWKLUGSDUWRIDVHULHVDVVRFLDWHGZLWKWKHH[SORUDWLRQRIQHZ DQWLEDFWHULDODJHQWVDQGLWGLVFXVVHVWKHFRPSRXQGVEHORQJLQJWRWKHJURXSRITXLQRORQHVDQGVXEVWDQFHVSRV - VHVVLQJDK\EULGVWUXFWXUHFRPSRVHGRIWKHTXLQRORQHPROHFXOHDQGRWKHUFRPSRXQGV (OHYHQQHZVXEVWDQFHVDWWKHVWDJHRIFOLQLFDOWULDOVDUHSUHVHQWHG7KUHHRIWKHPEHORQJWRWKHJURXSRIQRQ IOXRULQDWHGTXLQRORQH QHPRQR[DFLQR]HQR[DFLQDQG.53$0 ; ZKLOHVL[DUHWKHTXLQRORQHVFRQWDLQLQJ IOXRULQHDWRPDWSRVLWLRQRIWKHFDUERQDWRPLQWKHTXLQROLQHULQJ ]DERIOR[DFLQILQDIOR[DFLQGHODIOR[DFLQ -1-4:&.DQG.3, 7KHUHPDLQLQJWZRFRPSRXQGVSRVVHVVDK\EULGFRQVWUXFWLRQFRPSRVHGRIWKH TXLQRORQHVWUXFWXUHDQGRWKHUPROHFXOHV FDGD]ROLGDQG&%5 7KHUHLVDFKDQFHLQWKHQHDUIXWXUHWKDW WKHSUHVHQWHGFRPSRXQGVFDQH[WHQGWKHUDQJHRIH[LVWLQJDQWLEDFWHULDOGUXJVDQGSURYLGHDQDOWHUQDWLYHWRFXU - UHQWO\DYDLODEOHPHGLFLQDOSURGXFWV
.H\ZRUGV novel antibiotics, quinolones, fluoroquinolones
The presented article is a continuation of the series 'XULQJWKLVWLPHWHQVRIWKRXVDQGVVXEVWDQFHVEHORQJ - ³/RRNLQJIRUWKHQHZSUHSDUDWLRQVIRUDQWLEDFWHULDOWKHU - ing to this group were synthesized, among them those apy”, which discusses the new compounds introduced SRVVHVVLQJIOXRULQHDWRPDWWKH&SRVLWLRQH[KLELWWKH LQWRWKHWUHDWPHQWRIEDFWHULDOGLVHDVHVLQWKHWZHQW\ILUVW KLJKHVWDQWLEDFWHULDODFWLYLW\7KLVPRGLILFDWLRQFDXVHG century, and those at the stage of clinical trials. The first the division of quinolones into four generations. The SDUWGLVFXVVHVWKHQHZDQWLPLFURELDODJHQWVWKDWKDYH first generation consists of non-fluorinated compounds received a marketing authorization (1), the second part DQGWKHRQO\IOXRURTXLQRORQHIOXPHTXLQHDSSOLFDEOHLQ RIWKHVHULHVSUHVHQWVDJURXSRIQHZȕODFWDPDQWLELRWLFV veterinary medicine. The next three generations possess DQGȕODFWDPDVHLQKLELWRUVDWWKHVWDJHRIFOLQLFDOWULDOV IOXRULQHDWRPEXWWKH\DUHGLIIHUHQWLDWHGE\WKHVSHF - 7KLVVHFWLRQSUHVHQWVQHZFKHPRWKHUDSHXWLFDJHQWV WUXPRIDQWLEDFWHULDODFWLYLW\7KHVHFRQGJHQHUDWLRQ from the non-fluorinated quinolones group, fluoroqui- RITXLQRORQHVLVFKDUDFWHUL]HGE\DQLQFUHDVHGDFWLYLW\ QRORQHVDQGK\EULGFRPSRXQGVFRQWDLQLQJPROHFXOHRI against Gram-negative strains and atypical pathogens quinolone in its structure. All of these compounds are (Mycoplasma pneumoniae , Legionella pneumophila currently at the stage of clinical trials. and Chlamydia), it is also effective against Pseudomo- nas aeruginosa and Mycobacterium tuberculosis . The WKLUGJHQHUDWLRQRIIOXRURTXLQRORQHVKDVEHHQXVHGLQ CHEMOTHERAPEUTICS FROM WKHWUHDWPHQWRILQIHFWLRQVFDXVHGE\*UDPSRVLWLYH QUINOLONES GROUP EDFWHULDPDLQO\VWUHSWRFRFFLDQGVWDSK\ORFRFFLXVXDOO\ resistant to the second generation. The third generation More than half a century has passed since the ac- of fluoroquinolones are more effective against atypical FLGHQWDOLQYHQWLRQRIQDOLGL[LFDFLGDE\SURGXFWRIWKH pathogens. Fourth generation of fluoroquinolones is synthesis of the antimalarial drug - chloroquine and also FKDUDFWHUL]HGE\DQLQFUHDVHGDFWLYLW\DJDLQVWDQDHURELF the first representative of the group of quinolones (3). DQGDW\SLFDOSDWKRJHQVDQGDOVR*UDPSRVLWLYHEDFWHULD
1DWLRQDO,QVWLWXWHRI3XEOLF+HDOWK±1DWLRQDO,QVWLWXWHRI+\JLHQH 456 Izabela Karpiuk, Stefan Tyski No 3
7KHTXLQRORQHVHIIHFWLYHQHVVLVFDXVHGE\WKHSUHV - past 10 years. Three new compounds: nemonoxacin, HQFHRIIROORZLQJJURXSV WKHFDUER[\ODW&SRVLWLRQ R]HQR[DFLQDQG.53$0 ;DUHDWWKHVWDJHRI DQGWKHFDUERQ\ODW&ZKLFKDUHQHFHVVDU\WRWKH clinical trials. WUDQVSRUWRIPROHFXOHVLQWRWKHEDFWHULDFHOODVZHOO Nemonoxacin 7* H[KLELWVDEURDGVSHFWUXP as to the formation of the complex of enzyme – DNA. RIDQWLEDFWHULDODFWLYLW\DJDLQVW*UDPSRVLWLYHEDFWHULD 7KHTXLQRORQHVDUHWKHRQO\EDFWHULFLGDOJURXS including penicillin-resistant and quinolone-resistant of compounds, whose mechanism of action involves strains of Streptococcus pneumoniae (PRSP, penicil- WKHGLUHFWLQKLELWLRQRIWKHEDFWHULDO'1$V\QWKHVLV,W lin-resistant S. pneumoniae ), Staphylococcus aureus RFFXUVDVDUHVXOWRIWKHLQKLELWLRQRIWZREDFWHULDOHQ - resistant to methicillin (MRSA, methicillin -resistant ]\PHV '1$J\UDVH WRSRLVRPHUDVH,, ±UHVSRQVLEOHIRU S. aureus ) and registered quinolones and vancomycin- negative helical supercoiling and DNA topoisomerase resistant enterococci (VRE). The lowest concentration IV – separating nucleotide strands chain (4). Creation RIWKHDQWLPLFURELDODJHQWLQKLELWLQJWKHYLVLEOHJURZWK
RIDQLUUHYHUVLEOHHQ]\PH±'1$FRPSOH[ZLWKFKHPR - RI PLFURELDOVWUDLQV 0,& 90 , Minimal Inhibi- WKHUDSHXWLFFDXVHVWKHLQKLELWLRQRIWKH'1$UHSOLFDWLRQ tory Concentration LVJP/DJDLQVWYDQFRP\FLQ process and rapid cell death. Despite the existence of intermediate and vancomycin-resistant S. aureus two connection points, most quinolones has an affinity Nemonoxacin is also effective against the Nocardia for only one of these enzymes. It is important that the VS 7KHDQWLEDFWHULDODFWLYLW\RIWKLVFRPSRXQGLV recently synthesized fluoroquinolones (gemifloxacin FRPSDUDEOHWROHYRIOR[DFLQDQGPR[LIOR[DFLQDJDLQVW DQGVLWDIOR[DFLQ ELQGWRERWKHQ]\PHVPDNLQJUHVLV - Gram-negative rods. The advantage of nemonoxacin, tance difficult to increase. when compared to other fluoroquinolones is reduced 7KHUHDUHVHYHUDOEDVLFPHFKDQLVPVRIEDFWHULDO VXVFHSWLELOLW\WRWKHGHYHORSPHQWRIUHVLVWDQFHEHFDXVH resistance to the chemotherapeutic agents from the qui- LWUHTXLUHVQRWZREXWWKUHHVLPXOWDQHRXVPXWDWLRQVRI nolones group: i) mutations of genes encoding enzymes GLIIHUHQWEDFWHULDOJHQHV gyrA , gyrB and parC . Chinese resulting in the loss of affinity of quinolone molecule to company TaiGen Biotechnology Co. Ltd. completed WKHHQ]\PHFRQQHFWLRQSRLQW LL SUHVHQFHRIPHPEUDQH phase II of clinical trials for safety and efficacy of pumps systems actively removing the compound from QHPRQR[DFLQLQWKHWUHDWPHQWRIGLDEHWLFIRRWLQIHFWLRQV WKHFHOO HIIOX[PHFKDQLVP ZKLFKFDQEHDFWLYDWHG Currently, this chemotherapeutic agent is in the third E\FRQWDFWQRWRQO\ZLWKWKHTXLQRORQHEXWDOVRZLWK phase of clinical trials in the treatment of community OLSRSKLOLFFRPSRXQGV HJSHWUROHXPK\GURFDUERQV - acquired pneumonia (CAP). Based on the results of ZKLFKLQGLFDWHVDVLJQLILFDQWFRQWULEXWLRQRIHQYLURQ - the study, it was found that nemonoxacin (at doses of mental contamination to the development of this kind PJDQGPJ DGPLQLVWHUHGRUDOO\RQFHGDLO\ RIUHVLVWDQFH LLL PRGLILFDWLRQRIWKHSHUPHDELOLW\RIWKH GLVSOD\VWKHVDIHW\SURILOHDQGHIILFDF\FRPSDUDEOHWR RXWHUPHPEUDQHLQ*UDPQHJDWLYHEDFWHULDE\FORVLQJ the levofloxacin (500 mg) in the treatment of CAP. the porin channels. Ozenoxacin 7 LVDFKHPRWKHUDSHXWLFDJHQWSRV - Fluoroquinolones from the third and fourth gen- VHVVLQJDQWLEDFWHULDODFWLYLW\DJDLQVW S. aureus isolates eration form an effective treatment option with a wide sensitive and resistant to methicillin and ofloxacin, VSHFWUXPRIDQWLPLFURELDODFWLYLW\IDYRUDEOHSKDUPD - Staphylococcus epidermidis including the strains resis- FRNLQHWLFVDQGODUJHQXPEHURIDSSURYHGWKHUDSHXWLF tant to ofloxacin, PRSP and Propionibacterium acnes .
LQGLFDWLRQV1HYHUWKHOHVVLWVKRXOGEHHPSKDVL]HGWKDW MIC90 values against those pathogens are 4-16 000-fold quinolones are used as a first-line drugs in exceptional lower in comparison to other fluoroquinolones such clinical situations only (4,6). In general, quinolones DVQDGLIOR[DFLQRIOR[DFLQOHYRIOR[DFLQDQGDQWLELRW - DUHDQDOWHUQDWLYHPHGLFLQHVZKLFKFDQEHXVHGZKHQ ics: clindamycin, erythromycin and gentamicin (10). the applied therapy is ineffective or the use of first-line According to the authors ozenoxacin is an effective GUXJVLVLPSRVVLEOHRULQDGYLVDEOH TXLQRORQHIRUWRSLFDODGPLQLVWUDWLRQZKLFKFDQEHXVHG 2IILFLDOUHJLVWHUVDQGGDWDEDVHRIFOLQLFDOWULDOVZHUH to treat the complicated skin and soft-tissue infections used as the main source of the information on the vari- and through its activity significantly reduce the time of RXVSKDVHVRIFOLQLFDOWULDOVRIFRPSRXQGVGHVFULEHG treatment (10). What is essential, the mechanism of ac- EHORZ WLRQRIWKLVFKHPRWKHUDSHXWLFFRPSRXQGLVEDVHGRQVL - PXOWDQHRXVDIILQLW\IRUERWKHQ]\PHV'1$J\UDVHDQG topoisomerase IV. Ferrer Internacional S.A. conducts NEW COMPOUNDS FROM NON- the phase III of clinical trials on efficacy and safety of FLUORINATED QUINOLONES GROUP R]HQR[DFLQFUHDPYHUVXVSODFHERLQWKHWUHDWPHQW RISDWLHQWVZLWKQRQEXOORXVRUEXOORXVLPSHWLJR7KH One non-fluorinated quinolone – garenoxacin (Ja- results of the phase II of the study revealed the efficacy, SDQ ZDVLQWURGXFHGWRWKHWUHDWPHQWRYHUWKH VDIHW\DQGWROHUDELOLW\RIR]HQR[DFLQLQSDWLHQWVZLWK No 3 New preparations for antibacterial therapy III. Quinolones secondarily infected traumatic lesions. What is more, electrocardiogram (13). Dong Wha Pharmaceutical Co. no photoallergic and phototoxic reactions or potential Ltd. conducts phase III of clinical trials evaluating the DOOHUJLHVKDYHEHHQREVHUYHG VDIHW\DQGHIILFDF\RI]DERIOR[DFLQ PJ IROORZLQJ 7KHFRPSRXQGQDPHG.53$0 ;LVDSRRUO\ PXOWLSOHRUDODGPLQLVWUDWLRQLQSDWLHQWVZLWKDFXWHEDF - XQGHUVWRRGVXEVWDQFHZLWKKLJKHIILFDF\DJDLQVW WHULDOH[DFHUEDWLRQVRIFKURQLFREVWUXFWLYHSXOPRQDU\ *UDPSRVLWLYHEDFWHULDLQFOXGLQJ056$VWUDLQV7KH disease. Unfortunately, the phase II of clinical trials company Kyorin Pharmaceutical Co. Ltd. leads in Ja- OHGE\,$623KDUPD,QFFRQFHUQLQJWKHDSSOLFDWLRQRI pan phase I of clinical trials on the application of this this compound in the treatment of community-acquired compound in oral administration. It is worth to mention, pneumonia with moderate intensity was suspended for WKDWWKH.53$0 <LVDQDFURQ\PGHWHUPLQLQJWKH financial reasons. SDUHQWHUDOSUHSDUDWLRQIRUPXODZKLFKLVH[SHFWHGWREH The feature that distinguishes finafloxacin (BAY35- introduced into a phase I of clinical trials (11). IURPRWKHU fluoroquinolones is a 4 fold increase in DQWLEDFWHULDODFWLYLW\ at pH 6.0 compared to pH . )LQDIOR[DFLQH[KLELWVDQRSWLPXP efficiency at acidic NEW COMPOUNDS FROM pH in the range 5.0-6.0. The MIC values in this pH FLUOROQUINOLONES range is -fold lower against Escherichia coli and Klebsiella pneumoniae strains IROG lower against In the recent years seven compounds among the S. aureus , including MRSA DQG -fold lower against chemotherapeutic agents from fluoroquinolones group Pseudomonas aeruginosa in comparison to ciprofloxa- have received an approval for marketing authorization: cin and levofloxacin (14). Finafloxacin causes also an EDORIOR[DFLQ .RUHD SD]XIOR[DFLQ -DSDQ effective eradication of Helicobacter pylori pathogens. JHPLIOR[DFLQ )'$ WRVXIOR[DFLQ -DSDQ The unique activity of this compound at low pH may VLWDIOR[DFLQ -DSDQ DQWRIOR[DFLQ &KLQD FRQWULEXWH to its usage in the treatment of lesions located DQGEHVLIOR[DFLQ )'$ &XUUHQWO\ within the urinary tract, gastric mucosa or skin. It should the following six compounds are undergoing clinical EHPHQWLRQHG that the efficiency of finafloxacin is also GHYHORSPHQW ]DERIOR[DFLQILQDIOR[DFLQGHODIOR[DFLQ high against the sensitive and resistant to ciprofloxacin -1-4:&.DQG.3, Acinetobacter baumannii strains causing opportunistic $QWLEDFWHULDODFWLYLW\RI]DERIOR[DFLQ ':D infections among hospitalized patients, especially those PB-101) is higher in comparison with ciprofloxacin, receiving intensive care (15). What is essential, during moxifloxacin and gemifloxacin against Gram-positive the study on the safety profile of this compound, any strains, including MRSA, methicillin-resistant coagu- adverse reactions considered as typical for fluoroquino- lase-negative staphylococci, Streptococcus pyogenes lones, such as electrocardiogram changes, neurotoxicity and Enterococcus faecalis . Particular efficacy against or K\SRJO\FHPLDZHUHQRWREVHUYHG . ,Q WKH Mer- S. pneumoniae mostly isolated from patients with lion 3KDUPDFHXWLFDOV *PE+ successfully completed community-acquired pneumonia (16-fold greater than two research projects at phase II of clinical trials. The FLSURIOR[DFLQDQGPR[LIOR[DFLQ VKRXOGEHQRWHG$O - first concerned an application of finafloxacin (400 mg) WKRXJKWKH]DERIOR[DFLQDFWLYLW\LVDELWORZHUWKDQWKH with amoxicillin (1000 mg) or esomeprazole (40 mg) activity of other fluoroquinolones against microorgan- in the treatment of H. pylori infections and the second isms from the Enterobacteriaceae family, it still remains project included an evaluation of the efficiency of fi- a very good efficacy against Gram-negative respiratory nafloxacin (300 mg) in the treatment of uncomplicated pathogens Haemophilus influenzae and Moraxella ca- urinary tract infections in the three-days therapy. tarrhalis (MIC 90 JP/DQGJP/ Delafloxacin 5;$%7 LVDFKHPRWKHUD - 7KHORZHVWFRQFHQWUDWLRQRIWKH]DERIOR[DFLQLQKLELWLQJ peutic agent highly effective against Gram-positive
WKHYLVLEOHJURZWKRIPLFURELDOVWUDLQV 0,& 50 , EDFWHULDFKDUDFWHUL]HGE\DZHDNDFLGLFQDWXUHRIWKH Minimal Inhibitory Concentration LV JP/ molecule. Due to this property, similar to finafloxacin, against Neisseria gonorrhoeae and this is a value com- LWFDQEHVXFFHVVIXOO\XVHGIRUWKHWUHDWPHQWRI S. au- SDUDEOHWRD]LWKURP\FLQEXWIROGORZHUZLWKUHVSHFW reus infections. It demonstrates a good tolerance in the WRFLSURIOR[DFLQ'XHWRWKHGRXEOHPHFKDQLVPRI acidic environment of pH 5.0-5.5 (16). The spectrum of ELQGLQJRIWKHPROHFXOHRI]DERIOR[DFLQWRWKHFRPSOH[ DQWLEDFWHULDODFWLYLW\RIGHODIOR[DFLQLQFOXGHVVHQVLWLYH
HQ]\PH±'1$WKHULVNRIGHYHORSPHQWRIEDFWHULDO and resistant to methicillin isolates of S. aureus . MIC 90 resistance significantly decreases. The studies on the YDOXHVDUH JP/DQGJP/UHVSHFWLYHO\ VDIHW\RI':DFRPSRXQGGRQRWUHYHDODQ\DGYHUVH which means that it is the one of the most efficient effects on the central nervous system, cardiovascular fluoroquinolones among those registered. Furthermore, system and respiratory system with the exception of in vitro VWXGLHVLQGLFDWHWKDWGHODIOR[DFLQLVIURPWR SRVVLEOHLPSDFWRQWKHSURORQJHG47LQWHUYDOLQDQ IROGPRUHHIIHFWLYHDJDLQVWOHYRIOR[DFLQUHVLVWDQW Izabela Karpiuk, Stefan Tyski No 3 strains of S. pneumoniae and S. epidermidis and from 4 salt of DPLQRJXDQLGLQRSHQWDQRLFDFLG (arginine) to 16-fold more effective against ciprofloxacin-resistant and the optical isomer S of nadifloxacin. Due to the isolates of E. coli and K. pneumoniae , in comparison fact, that the configuration S LVSULPDULO\UHVSRQVLEOH to moxifloxacin, gemifloxacin and withdrawn form the for WKHDQWLEDFWHULDODFWLYLW\:&.LV WR -fold market, due to toxicity: trovafloxacin and gatifloxacin. more effective than the racemic mixture of nadifloxacin. Unfortunately, delafloxacin does not have any activity :&. in parenteral administration completed phase against pathogens sensitive and resistant to registered II of clinical trials for the treatment of MRSA infections quinolones: Enterococcus faecium , E. faecalis , P. ae- led E\ Wockhardt Ltd. While, the compound GHVFULEHG ruginosa and Acinetobacter JHQXV 5LE;3KDU - E\ acronym :&. concerns an oral form of the this maceuticals, Inc. completed phase II of clinical trials drug, which also completed phase II of clinical trials evaluating the usage of this compound in the treatment in the therapy of the same diseases like the previous RIDFXWHEDFWHULDOVNLQDQGVNLQVWUXFWXUHLQIHFWLRQV form $%666, LQ1RYHPEHU The compound KPI-10 :4 LVLQWKHHDUOLHVW Compound named JNJ 4 -1- DVZHOO stage of clinical trials among the other fluoroquinolones: DVFHUWDLQRWKHUIOXRURTXLQRORQHVH[KLELWVEDFWHULFLGDO SKDVH,VWXGLHVFRQGXFWHGE\.DOLGH[3KDUPDFHXWLFDOV DFWLYLW\DJDLQVWDEURDGVSHFWUXPRI*UDPSRVLWLYHDQG $VGHVFULEHGFRPSRXQGVWKH.3,KDVDQDQWLEDFWH -
*UDPQHJDWLYHEDFWHULD0,& 50 YDOXHVDUHJP/ ULDODFWLYLW\DJDLQVWDEURDGVSHFWUXPRI*UDPSRVLWLYH DJDLQVWPHWKLFLOOLQVXVFHSWLEOH S. aureus DQGJ DQG*UDPQHJDWLYHEDFWHULDLQFOXGLQJVWUDLQVUHVLVWDQWWR mL against MRSA. Pathogens were isolated from the FXUUHQWO\DYDLODEOHFKHPRWKHUDSHXWLFDJHQWVIURPWKLV
SDWLHQWVZLWK$%666,7KHFRPSRXQG-1-4VKRZV group. Based on MIC 90 YDOXHDQDO\VLVLWZDVREVHUYHG a higher activity than moxifloxacin (16 times), levo- that the compound is several times more effective IOR[DFLQDQGFLSURIOR[DFLQ DWOHDVWWLPHV DJDLQVW against sensitive and resistant pathogens of S. aureus , S. S. pneumoniae ,QFDVHRI*UDPQHJDWLYHEDFWHULDWKH epidermidis , S. pneumoniae , S. pyogenes , Streptococcus values of MIC 50 IRUFRPSRXQG-1-4DUHIROORZLQJ agalactiae and E. faecalis EXWRPLWWLQJ E. faecium in JP/DJDLQVW H. influenzae JP/DJDLQVW comparison to levofloxacin, ciprofloxacin, moxifloxa- M. catarrhalis DQGJP/DJDLQVW N. gonor- FLQDQGJDWLIOR[DFLQ .3,DOVRGHPRQVWUDWHV rhoeae (19). As regards the mechanism of action of improved efficacy against resistant to ciprofloxacin
WKHFRPSRXQG-1-4LWDOVRKDVDQDIILQLW\IRUERWK and penicillin N. gonorrhoeae strains (MIC 50/90 values enzymes at the same time, moreover preclinical studies JP/ have disclosed, it is not removed from the cells using .DOLGH[3KDUPDFHXWLFDOVFRPSDQ\LQIRUPVDERXW efflux system. Phase II of clinical trials concerning the WKHH[FHOOHQWVDIHW\SURILOHIDYRUDEOHSKDUPDFRNLQHWLFV VDIHW\HIILFDF\DQGWROHUDQFHRI-1- FRP - and efficacy of the compound KPI-10 in in vivo studies. SRXQG PJ FRPSDUHGWROLQH]ROLGLQWKHWUHDWPHQW of patients with complicated skin and soft-tissue infec- ANTIBACTERIAL HYBRID COMPOUNDS WLRQVZHUHFRPSOHWHGLQ-DQXDU\+RZHYHUSKDVH II of clinical trials evaluating usage of this compound CONTAINING THE QUINOLONE in the treatment of patients requiring hospitalization STRUCTURE for community-acquired pneumonia were suspended. ,QVXIILFLHQWQXPEHURISDUWLFLSDQWVLQFOXGHGLQWKH One of the recent achievements against multidrug- UHFUXLWPHQWSURFHVVZDVJLYHQDVWKHRIILFLDOUHDVRQE\ UHVLVWDQWEDFWHULDLVWKHGHYHORSPHQWRIK\EULGFKHPR - PDUNHWLQJDXWKRUL]DWLRQKROGHU WKHSURFFHVVKDVQR therapeutic agents, which consist of two compounds effect on the safety and efficacy of the product. Both ZLWKGLIIHUHQWPHFKDQLVPVRIDFWLRQFRPELQHGZLWK projects involved the oral formula of the drug and were each other. FRQGXFWHGE\)XULH[3KDUPDFHXWLFDOV,QF Cadazolid $&7 LVDK\EULGRIWZRSKDUPDFR - The compound :&. LVFKDUDFWHUL]HGE\KLJKHU phores from the oxazolidinones and quinolones group. than registered fluoroquinolones, efficacy against $NH\HOHPHQWRIWKHFRPELQDWLRQRIWKHVHWZRSKDUPD - resistant to methicillin and vancomycin strains of S. FRSKRUHVZDVWRHQVXUHDSURSHUFRPELQDWLRQRIWKHVH aureus , staphylococci resistant to FXUUHQWO\DYDLODEOH VWUXFWXUHVLQRUGHUWRREWDLQWKHRSWLPXPDQWLPLFURELDO quinolones and DQDHURELFEDFWHULD0,& 50/90 values are DFWLYLW\ 7KHFRPSDQ\$FWHOLRQ/WGFRPSOHWHG JP/ and 1 JP/ against hospital-acquired and phase II of clinical trials concerning the efficacy and community-acquired S. aureus isolates, respectively safety of the cadazolid in the therapy of Clostridium In addition, the compound :&.H[KLELWV in difficile DVVRFLDWHGGLDUUKHDLQ2FWREHU7KHUHVXOWV vitro and in vivo DQWLEDFWHULDODFWLYLW\VLPLODU to levo- of the study confirmed the good tolerance, efficacy floxacin against S. pneumoniae sensitive to registered and safety of twice daily administered oral formula of quinolones 6WUXFWXUDOO\ , it exists as a hydrated cadazolid. No 3 New preparations for antibacterial therapy III. Quinolones 459
The compound named CBR LVDK\EULGFRQ - UHVLVWDQFHDQGXQGRXEWHGO\KRSHIRUVXFFHVVDJDLQVW sisting of two pharmacophores from the rifamycins and multidrug-resistance pathogens. At this point, we can TXLQRORQHVJURXS,WVKRZVDQDQWLPLFURELDODFWLYLW\RI just wait and hope for the development of research in ULIDPSLFLQGXHWRWKHLQKLELWLRQRI51$SRO\PHUDVHDV WKHILHOGRIHIIHFWLYHK\EULGFRPSRXQGVDQGH[SHFWDOVR well as an affinity for DNA gyrase and topoisomerase IV, successful results. so it is effective against strains resistant to rifampicin. 8QIRUWXQDWHO\WKH&%5 FRPSRXQGGRHVQRWUHYHDO any activity against pathogens resistant to currently REFERENCES DYDLODEOHTXLQRORQHVDQGDOVRDJDLQVW*UDPQHJDWLYH EDFWHULD %DVHGRQWKH in vivo VWXGLHV0%LR7HFK .DUSLXN,7\VNL63RV]XNLZDQLHQRZ\FKSUHSDUDWyZGR L.P. company leads phase I of clinical trials concerning WHUDSLLSU]HFLZEDNWHU\MQHM,1RZHDQW\ELRW\NLLFKHPL - WKHXVDJHRIWKLVK\EULGLQWKHWUHDWPHQWRISHUVLVWHQW RWHUDSHXW\NLGRSXV]F]RQHGRREURWX3U]HJO(SLGHPLRO VWDSK\ORFRFFDOLQIHFWLRQV7KHSUREDEOHUHDVRQIRUWKH .DUSLXN,7\VNL6/RRNLQJIRUWKHQHZSUHSDUDWLRQV ODFNRIDQWLEDFWHULDODFWLYLW\RIWKHK\EULGFRPSRXQGV IRUDQWLEDFWHULDOWKHUDS\,,&OLQLFDOWULDOV QHZȕODFWDP DJDLQVW*UDPQHJDWLYHEDFWHULDLVWKHUHGXFHGDELOLW\ DQWLELRWLFVDQGȕODFWDPDVHLQKLELWRUV3U]HJO(SLGHPLRO RISDVVLQJWKURXJKWKHRXWHUPHPEUDQHUHVXOWLQJIURP WKHSDUWLFOHVL]H+RZHYHUWKHXQGRXEWHGDGYDQWDJHRI 3. Michalska K, Pajchel G, Tyski S. Charakterystyka K\EULGFRPSRXQGVOLHVLQFUHDWLQJH[WUHPHO\GLIILFXO - FKLQRORQyZ&]ĊĞü,%XGRZDFKHPLF]QD:áDĞFLZRĞFL ties for microorganisms to induce mutations, which is IDUPDNRORJLF]QH0LNURELRORJLD0HG\F\QD the chance to stop a dangerous trend of increasing drug 19 resistance. 4. Michalska K, Pajchel G, Tyski S. Charakterystyka FKLQRORQyZ&]ĊĞü,,0HFKDQL]PG]LDáDQLD2SRUQRĞü GUREQRXVWURMyZ7HUDSLD']LDáDQLDQLHSRĪąGDQH0LN - CONCLUSIONS URELRORJLD0HG\F\QD 5. Laudy AE. 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At least ten of these agents are currently at the Taiwan of the in vitro activities of nemonoxacin, tigecy- VWDJHRIFOLQLFDOWULDOVDQGHLJKWKDYHEHHQLQWURGXFHG FOLQHGRULSHQHPDQGRWKHUDQWLPLFURELDODJHQWVDJDLQVW to treatment in the recent 11 years. clinical isolates of various Nocardia VSHFLHV$QWLPLFURE $PRQJVXFKDODUJHJURXSRIDFWLYHVXEVWDQFHV± $JHQWV&KHPRWKHU candidates for medicinal products, nemonoxacin with 10. Yamakawa T, Mitsuyama J, Hayashi K. 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