Anti-francisella agents

Abstract

A series of celecoxib derivatives defined by Formula I: were prepared and evaluated for their ability to inhibit the gram-negative bacteria Francisella tularensis . Pharmaceutical compositions including celecoxib derivatives and their use in methods for treating or preventing infection by Francisella tularensis in a subject are described.

1 . A method of treating or preventing infection by  Francisella tularensis  in a subject, comprising administering a therapeutically effective amount of a composition including a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of hydrogen, amino, amido, sulfonamidyl, methylsulfinyl, and ethylsulfinyl moieties, 
 
         and
 R 2  is an aryl group, and wherein R 2  is optionally substituted at substitutable positions with one of more moieties independently selected from halo, lower alkyl, lower haloalkyl, lower hydroxyalkyl, hydroxyl, nitro, amino, carboxyl, and cyano; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the R 2  aryl group is selected from the group consisting of phenyl, naphthyl, biphenyl, anthracenyl, and phenanthracenyl aryl groups. 
     
     
         3 . The method of  claim 2 , wherein the optional substituting moieties for R 2  are independently selected from bromo, chloro, fluoro, methoxy, trifluoromethyl, methyl, ethyl, propyl, and butyl. 
     
     
         4 . The method of  claim 1 , wherein the compound is selected from the group consisting of:
 Celecoxib;   4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-benzamide;   4-[5-(4′-chloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(3′,5′-dichloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4′-methyl-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[3-trifluoromethyl-5-(4′-trifluoromethyl-biphenyl-4-yl)-pyrazol-1-yl]-benzamide;   4-[5-(3′,5′-dimethyl-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4′-tert-Butyl-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4′-butyl-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-(5-anthracen-9-yl-3-trifluoromethyl-pyrazol-1-yl)-benzamide;   4-[5-(4-butyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4′-chloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesulfonamide;   4-[5-(3′,4′,5′-trichloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesulfonamide;   4-(5-naphthalen-1-yl-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;   5-(4-fluoro-phenyl)-1-(4-ethanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole;   1-(4-methanesulfonyl-phenyl)-5-(4′-methyl-biphenyl-4-yl)-3-trifluoromethyl-1H-pyrazole;   4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine;   4-[5-(3′,4′,5′-trichloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-phenylamine;   4-(5-naphthalen-1-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine;   4-[5-(6-methoxy-naphthalen-2-yl)-3-trifluoromethyl-pyrazol-1-yl]-phenylamine;   4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine; and   5-phenanthren-3-yl-1-phenyl-3-trifluoromethyl-1H-pyrazole;   and their pharmaceutically acceptable salts.   
     
     
         5 . The method of  claim 1 , wherein the compound is selected from the group consisting of:
 Celecoxib;   4-[5-(4′-chloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4′-chloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesulfonamide;   4-[5-(3′,4′,5′-trichloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesulfonamide;   4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine; and   4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine;   and their pharmaceutically acceptable salts.   
     
     
         6 . The method of  claim 1 , wherein the compound is 4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method of  claim 1 , wherein the  Francisella tularensis  infection is inhibited in macrophage cells without significant toxicity to the macrophage cells. 
     
     
         8 . The method of  claim 1 , wherein the  Francisella tularensis  is antibiotic resistant. 
     
     
         9 . The method of  claim 1 , wherein the subject is a human. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . A compound selected from the group consisting of:
 4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-benzamide;   4-[5-(4′-methyl-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4′-butyl-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4-butyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   5-(4-fluoro-phenyl)-1-(4-ethanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole;   1-(4-methanesulfonyl-phenyl)-5-(4′-methyl-biphenyl-4-yl)-3-trifluoromethyl-1H-pyrazole;   4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine;   4-[5-(3′,4′,5′-trichloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-phenylamine;   4-(5-naphthalen-1-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine;   4-[5-(6-methoxy-naphthalen-2-yl)-3-trifluoromethyl-pyrazol-1-yl]-phenylamine;   4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine; and   5-phenanthren-3-yl-1-phenyl-3-trifluoromethyl-1H-pyrazole;   and their pharmaceutically acceptable salts.   
     
     
         14 . The compound of  claim 13 , wherein the compound is selected from the group consisting of:
 4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine; and   4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine;   and their pharmaceutically acceptable salts.   
     
     
         15 . The compound of  claim 13 , wherein the compound is 4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine or a pharmaceutically acceptable salt thereof. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . A pharmaceutical composition, wherein the compound is selected from the group consisting of:
 4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-benzamide;   4-[5-(4′-methyl-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4′-butyl-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   4-[5-(4-butyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzamide;   5-(4-fluoro-phenyl)-1-(4-ethanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole;   1-(4-methanesulfonyl-phenyl)-5-(4′-methyl-biphenyl-4-yl)-3-trifluoromethyl-1H-pyrazole;   4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine;   4-[5-(3′,4′,5′-trichloro-biphenyl-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-phenylamine;   4-(5-naphthalen-1-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine;   4-[5-(6-methoxy-naphthalen-2-yl)-3-trifluoromethyl-pyrazol-1-yl]-phenylamine;   4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine; and   5-phenanthren-3-yl-1-phenyl-3-trifluoromethyl-1H-pyrazole.   and their pharmaceutically acceptable salts.   
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the compound is selected from the group consisting of:
 4-(5-biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine; and   4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine;   and their pharmaceutically acceptable salts.   
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein the compound is 4-[5-(4′-bromo-biphenyl-4-yl)-3-trifluoromethyl-pyrazolyl]-phenylamine or a pharmaceutically acceptable salt thereof.