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Antimycobacterial Activities of Novel 5-(1H-1,2,3-Triazolyl)Methyl Oxazolidinones.

Phillips OA, Udo EE, Varghese R - Tuberc Res Treat (2012)

Bottom Line: Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC(90): < 0.2 to 0.422 μg/mL) and arylcarbonyl (IC(90): < 0.2 to 2.103 μg/mL) groups at the piperazine 4N-position-displayed potent antimycobacterium activities, comparable to the methanesulfonyl (IC(90): < 0.2 μg/mL) analog, linezolid (IC(90): < 0.2 μg/mL), and isoniazid (IC(90): < 0.034 μg/mL).The furanylcarbonyl derivative also displayed potent activity, while the arylsulfonyl analogs were inactive.Of the triazolyl oxazolidinones, the morpholino (PH-27) derivative with medium bioavailability in plasma was most active in vivo, but relatively less efficacious than isoniazid.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.

ABSTRACT
The antibacterial activities of a series of triazolyl oxazolidinones against Mycobacterium tuberculosis strain in vitro and in vivo in a mice model are presented. Most active compounds were noncytotoxic against VERO cells with acceptable selectivity indexes (SI) as measures of compound tolerability. Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC(90): < 0.2 to 0.422 μg/mL) and arylcarbonyl (IC(90): < 0.2 to 2.103 μg/mL) groups at the piperazine 4N-position-displayed potent antimycobacterium activities, comparable to the methanesulfonyl (IC(90): < 0.2 μg/mL) analog, linezolid (IC(90): < 0.2 μg/mL), and isoniazid (IC(90): < 0.034 μg/mL). The furanylcarbonyl derivative also displayed potent activity, while the arylsulfonyl analogs were inactive. Of the triazolyl oxazolidinones, the morpholino (PH-27) derivative with medium bioavailability in plasma was most active in vivo, but relatively less efficacious than isoniazid.

No MeSH data available.


Related in: MedlinePlus

Chemical structure of oxazolidinone antibacterial agents and novel antimycobacterial agents.
© Copyright Policy - open-access
Related In: Results  -  Collection


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fig1: Chemical structure of oxazolidinone antibacterial agents and novel antimycobacterial agents.

Mentions: A number of drugs, namely, isoniazid, rifampicin, ethambutol, and pyrazinamide are often administered over a prolonged period of time and may lead to the development of resistant strains due to patient-poor compliance among other factors. The development and spread of resistant M. tuberculosis, pose a vital challenge to the control of TB world-wide. In recent years, the emergence and spread of resistant M. tuberculosis strains has fuelled the TB epidemic by making it more difficult to treat. Multidrug-resistant (MDR) TB, which is resistant to the first line anti-TB agents, namely, isoniazid and rifampicin are increasing with >500,000/yr new cases of MDR-TB worldwide [3, 4]. Extensively drug-resistant (XDR) TB, resistant to first line anti-TB agents, namely, isoniazid, rifampicin, fluoroquinolones, and one of three injectable drugs, such as capreomycin, kanamycin, or amikacin is awfully difficult to treat and is considered a worldwide threat to TB control [3, 4]. These statistics serve as impetus for development of more effective and safer anti-TB drugs [5]. For more than 40 years, there has been a drought of new anti-TB drugs. However, more recently, there are increasing reports of newer agents demonstrating activity against drug-resistant M. tuberculosis strains [5–8]. Among these new agents are the oxazolidinones (linezolid—LZD; and PNU-100480; Figure 1), diarylquinoline (TMC-207; Figure 1), the nitroimidazole-oxazole (OPC-67683; Figure 1), the nitroimidazo-oxazine (PA-824, Figure 1), and some quinolone class of compounds. Linezolid (LZD; Figure 1), a prototypical oxazolidinone used in the clinic to treat gram-positive bacterial infections, the thiomorpholino derivative of LZD (PNU-100480; Figure 1), and others in this class, have demonstrated activity against susceptible and drug-resistant M. tuberculosis. Our laboratories have been interested in the synthesis of triazolylmethyl oxazolidinones of general structures PH-27, 1, 2, and 3 (Figure 1) with antibacterial activity [9–12]. Studies from other laboratories and ours have shown that the triazolyl oxazolidinones have potent activity against gram-positive bacterial species [9–14], comparable or superior to linezolid in vitro, thus affirming the bioisosteric replacement of the C5 acetamido functional group by the triazolyl moiety. On the basis of the potent antibacterial activities of the triazolyl oxazolidinones and the demonstrated antimycobacterium activities of representative oxazolidinones, namely, LZD and PNU-100480, we evaluated the antiMycobacterium tuberculosis activity of selected novel triazolylmethyl oxazolidinones synthesized from our laboratories. Therefore, this study outlines the in vitro and in vivo antimycobacterial activity of selected triazolylmethyl oxazolidinones and to establish observable qualitative structure-activity relationships.


Antimycobacterial Activities of Novel 5-(1H-1,2,3-Triazolyl)Methyl Oxazolidinones.

Phillips OA, Udo EE, Varghese R - Tuberc Res Treat (2012)

Chemical structure of oxazolidinone antibacterial agents and novel antimycobacterial agents.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3345221&req=5

fig1: Chemical structure of oxazolidinone antibacterial agents and novel antimycobacterial agents.
Mentions: A number of drugs, namely, isoniazid, rifampicin, ethambutol, and pyrazinamide are often administered over a prolonged period of time and may lead to the development of resistant strains due to patient-poor compliance among other factors. The development and spread of resistant M. tuberculosis, pose a vital challenge to the control of TB world-wide. In recent years, the emergence and spread of resistant M. tuberculosis strains has fuelled the TB epidemic by making it more difficult to treat. Multidrug-resistant (MDR) TB, which is resistant to the first line anti-TB agents, namely, isoniazid and rifampicin are increasing with >500,000/yr new cases of MDR-TB worldwide [3, 4]. Extensively drug-resistant (XDR) TB, resistant to first line anti-TB agents, namely, isoniazid, rifampicin, fluoroquinolones, and one of three injectable drugs, such as capreomycin, kanamycin, or amikacin is awfully difficult to treat and is considered a worldwide threat to TB control [3, 4]. These statistics serve as impetus for development of more effective and safer anti-TB drugs [5]. For more than 40 years, there has been a drought of new anti-TB drugs. However, more recently, there are increasing reports of newer agents demonstrating activity against drug-resistant M. tuberculosis strains [5–8]. Among these new agents are the oxazolidinones (linezolid—LZD; and PNU-100480; Figure 1), diarylquinoline (TMC-207; Figure 1), the nitroimidazole-oxazole (OPC-67683; Figure 1), the nitroimidazo-oxazine (PA-824, Figure 1), and some quinolone class of compounds. Linezolid (LZD; Figure 1), a prototypical oxazolidinone used in the clinic to treat gram-positive bacterial infections, the thiomorpholino derivative of LZD (PNU-100480; Figure 1), and others in this class, have demonstrated activity against susceptible and drug-resistant M. tuberculosis. Our laboratories have been interested in the synthesis of triazolylmethyl oxazolidinones of general structures PH-27, 1, 2, and 3 (Figure 1) with antibacterial activity [9–12]. Studies from other laboratories and ours have shown that the triazolyl oxazolidinones have potent activity against gram-positive bacterial species [9–14], comparable or superior to linezolid in vitro, thus affirming the bioisosteric replacement of the C5 acetamido functional group by the triazolyl moiety. On the basis of the potent antibacterial activities of the triazolyl oxazolidinones and the demonstrated antimycobacterium activities of representative oxazolidinones, namely, LZD and PNU-100480, we evaluated the antiMycobacterium tuberculosis activity of selected novel triazolylmethyl oxazolidinones synthesized from our laboratories. Therefore, this study outlines the in vitro and in vivo antimycobacterial activity of selected triazolylmethyl oxazolidinones and to establish observable qualitative structure-activity relationships.

Bottom Line: Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC(90): < 0.2 to 0.422 μg/mL) and arylcarbonyl (IC(90): < 0.2 to 2.103 μg/mL) groups at the piperazine 4N-position-displayed potent antimycobacterium activities, comparable to the methanesulfonyl (IC(90): < 0.2 μg/mL) analog, linezolid (IC(90): < 0.2 μg/mL), and isoniazid (IC(90): < 0.034 μg/mL).The furanylcarbonyl derivative also displayed potent activity, while the arylsulfonyl analogs were inactive.Of the triazolyl oxazolidinones, the morpholino (PH-27) derivative with medium bioavailability in plasma was most active in vivo, but relatively less efficacious than isoniazid.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.

ABSTRACT
The antibacterial activities of a series of triazolyl oxazolidinones against Mycobacterium tuberculosis strain in vitro and in vivo in a mice model are presented. Most active compounds were noncytotoxic against VERO cells with acceptable selectivity indexes (SI) as measures of compound tolerability. Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC(90): < 0.2 to 0.422 μg/mL) and arylcarbonyl (IC(90): < 0.2 to 2.103 μg/mL) groups at the piperazine 4N-position-displayed potent antimycobacterium activities, comparable to the methanesulfonyl (IC(90): < 0.2 μg/mL) analog, linezolid (IC(90): < 0.2 μg/mL), and isoniazid (IC(90): < 0.034 μg/mL). The furanylcarbonyl derivative also displayed potent activity, while the arylsulfonyl analogs were inactive. Of the triazolyl oxazolidinones, the morpholino (PH-27) derivative with medium bioavailability in plasma was most active in vivo, but relatively less efficacious than isoniazid.

No MeSH data available.


Related in: MedlinePlus