Novel inhibitors of bacterial biofilms and related methods

Abstract

Certain multi-cyclic compounds and compositions thereof are useful for reducing or inhibiting the growth of bacterial biofilms and for controlling bacterial biofilm infections. Such compounds and compositions are also useful in methods for reducing or inhibiting the growth of biofilms and for controlling bacterial biofilm infections involving biofilms.

What is claimed is: 
     
         1 - 62 . (canceled) 
     
     
         63 . A compound corresponding to the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R1 is selected from the group consisting of hydrogen, methyl, halide, lower haloalkyl, nitrile, lower alkyl nitrile, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, lower cycloalkyl, lower cycloalkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; wherein R 2  is selected from the group consisting of carboxyl, amide, hydroxyamide, methylamide, —CH 2 N(CH 3 ) 2 , —CH 2 NR 6 R 7 , 
       
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of hydrogen and methyl; wherein one of R 4  and R 5  is hydrogen and the other is methyl; wherein R 6  and R 7  are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and butyl; wherein R 8  is selected from the group consisting of hydroxyl, amino, —N(CH 3 ) 2 , and —NHCH 3 ; wherein R 9  is selected from the group consisting of hydrogen, halide, lower alkyl, lower alkenyl, lower alkynyl, morpholinyl, piperazinyl, lower alkyl piperazinyl, heterocycloalkyl, lower cycloalkyl, lower cycloalkenyl; and lower alkyl, lower alkenyl, and lower alkynyl optionally substituted with moieties selected from the group consisting of hydroxyl, amino, lower aminoalkyl, halide, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, lower alkylcarbonylamino, carboxyl, amide, hydroxyamide, —CONHCH 3 , —NHCONH 2 , —SO 2 NH 2 , —SO 2 CH 3 , —NHCOCH 3 , —NHCSNH 2 , and —NHSO 2 CH 3 ; and wherein R 10  and R 11  together with the carbon atoms to which they are attached form an aromatic N-heterocycle which is substituted or not selected from the group consisting of indole, imidazole, quinoline, isoquinoline, pyridine, triazine, pyrazine, pyrimidine, pyridazine, isoindole, pyrrole, benzimidazole, purine, pyrazole, benzopyrazole, indazole, quinoxaline, acridine, quinazoline, indolizine, carbazole and cinnoline; and salts thereof. 
       
     
     
         64 . A compound according to claim  1 , wherein the compound corresponds to the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, methyl, halide, lower haloalkyl, nitrile, lower alkyl nitrile, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, lower cycloalkyl, lower cycloalkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; wherein R 2  is selected from the group consisting of carboxyl, amide, hydroxyamide, methylamide, —CH 2 N(CH 3 ) 2 , —CH 2 NR 6 R 7 , 
       
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of hydrogen and methyl; wherein one of R 4  and R 5  is hydrogen and the other is methyl; wherein R 6  and R 7  are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and butyl; wherein R 8  is selected from the group consisting of hydroxyl, amino, —N(CH 3 ) 2 , and —NHCH 3 ; and wherein R 9  is selected from the group consisting of hydrogen, halide, lower alkyl, lower alkenyl, lower alkynyl, morpholinyl, piperazinyl, lower alkyl piperazinyl, heterocycloalkyl, lower cycloalkyl, lower cycloalkenyl; and lower alkyl, lower alkenyl, and lower alkynyl optionally substituted with moieties selected from the group consisting of hydroxyl, amino, lower aminoalkyl, halide, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, lower alkylcarbonylamino, carboxyl, amide, hydroxyamide, —CONHCH 3 , —NHCONH 2 , —SO 2 NH 2 , —SO 2 CH 3 , —NHCOCH 3 , —NHCSNH 2 , and —NHSO 2 CH 3 ; and salts thereof. 
       
     
     
         65 . A compound according to  claim 63  wherein R 1  is selected from the group consisting of methyl, halide, lower haloalkyl, nitrile, lower alkyl nitrile, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, lower cycloalkyl, lower cycloalkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, preferably R 1  is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thienyl, furanyl, furazanyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, 3H-indolyl, isoindolyl, indolinyl, indolizinyl, indazolyl, dihydroindolyl, tetrahydroindolyl, purinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzothienyl, furopyridinyl, phthalazinyl, napthyridinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridinyl, and tetrahydropyrrolopyridinyl optionally substituted from moieties selected from the group consisting of lower alkyl, halide, lower haloalkyl, hydroxyl, amino, lower aminoalkyl, lower hydroxyalkyl, nitrile, lower alkyl nitrile, lower alkyl ethers, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, lower alkylcarbonylamino, and thioalkyl. 
     
     
         66 . A compound according to  claim 64  wherein the compound corresponds to the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, halide, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkyl, lower cycloalkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, preferably R 1  is hydrogen. 
       
     
     
         67 . A compound according to  claim 66  wherein R 1  is selected from the group consisting of halide, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, preferably R 1  is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thienyl, furanyl, furazanyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, 3H-indolyl, isoindolyl, indolinyl, indolizinyl, indazolyl, dihydroindolyl, tetrahydroindolyl, purinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzothienyl, furopyridinyl, phthalazinyl, napthyridinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridinyl, and tetrahydropyrrolopyridinyl optionally substituted from moieties selected from the group consisting of lower alkyl, halide, lower haloalkyl, hydroxyl, amino, lower aminoalkyl, lower hydroxyalkyl, nitrile, lower alkyl nitrile, lower alkyl ethers, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, lower alkylcarbonylamino, and thioalkyl. 
     
     
         68 . A compound according to  claim 64  wherein R 1  is selected from the group consisting of hydrogen, halide, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, substituted aryl, lower cycloalkenyl, aryl, heteroaryl, and substituted heteroaryl; and wherein R 2  is selected from the group consisting of amide, hydroxyamide, methylamide, —CH 2 N(CH 3 ) 2 , —CH 2 NR 6 R 7 , 
       
         
           
           
               
               
           
         
       
     
     
         69 . A compound according to  claim 68  wherein R 1  is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thienyl, furanyl, furazanyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, 3H-indolyl, isoindolyl, indolinyl, indolizinyl, indazolyl, dihydroindolyl, and tetrahydroindolyl optionally substituted from moieties selected from the group consisting of lower alkyl, halide, lower haloalkyl, hydroxyl, amino, lower aminoalkyl, lower hydroxyalkyl, nitrile, lower alkyl nitrile, lower alkyl ethers, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, lower alkylcarbonylamino, and thioalkyl. 
     
     
         70 . A compound according to  claim 64  wherein R 2  is 
       
         
           
           
               
               
           
         
         wherein R 8  is selected from the group consisting of hydroxyl and amino; and wherein R 9  is selected from the group consisting of hydrogen, halide, lower alkyl, lower alkenyl, lower alkynyl, morpholinyl, piperazinyl, lower alkyl piperazinyl, heterocycloalkyl, lower cycloalkyl, lower cycloalkenyl; and lower alkyl, lower alkenyl, and lower alkynyl optionally substituted with moieties selected from the group consisting of hydroxyl, amino, lower aminoalkyl, halide, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, lower alkylcarbonylamino, carboxyl, amide, hydroxyamide, —CONHCH 3 , —NHCONH 2 , —SO 2 NH 2 , —SO 2 CH 3 , —NHCOCH 3 , —NHCSNH 2 , and —NHSO 2 CH 3  preferably R 9  is hydrogen; and salts thereof. 
       
     
     
         71 . A compound according to  claim 70  wherein R 1  is selected from the group consisting of heteroaryl and substituted heteroaryl, wherein R 2  is 
       
         
           
           
               
               
           
         
         wherein R 8  is selected from the group consisting of hydroxyl and amino; and wherein R 9  is hydrogen. 
       
     
     
         72 . A compound according to  claim 64  wherein the compound corresponds to the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, methyl, halide, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, preferably R 1  is selected from the group consisting of heteroaryl and substituted heteroaryl. 
       
     
     
         73 . A compound according to  claim 63 , wherein the compound corresponds to the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R1 is selected from the group consisting of hydrogen, methyl, halide, nitrile, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; wherein R3 is selected from the group consisting of hydrogen and methyl; and wherein one of R4 and R5 is hydrogen and the other is methyl; and salts thereof. 
       
     
     
         74 . A compound according to  claim 63  wherein the compound corresponds to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         75 . A method for inhibiting or reducing the formation or growth of a biofilm comprising contacting said biofilm or a cell capable of biofilm formation or growth with an effective amount of a compound or a composition comprising the compound corresponding to the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R1 is selected from the group consisting of hydrogen, methyl, halide, lower haloalkyl, nitrile, lower alkyl nitrile, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, lower cycloalkyl, lower cycloalkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; wherein R 2  is selected from the group consisting of carboxyl, amide, hydroxyamide, methylamide, —CH 2 N(CH 3 ) 2 , —CH 2 NR 6 R 7 , 
       
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of hydrogen and methyl; wherein one of R 4  and R 5  is hydrogen and the other is methyl; wherein R 6  and R 7  are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and butyl; wherein R 8  is selected from the group consisting of hydroxyl, amino, —N(CH 3 ) 2 , and —NHCH 3 ; wherein R 9  is selected from the group consisting of hydrogen, halide, lower alkyl, lower alkenyl, lower alkynyl, morpholinyl, piperazinyl, lower alkyl piperazinyl, heterocycloalkyl, lower cycloalkyl, lower cycloalkenyl; and lower alkyl, lower alkenyl, and lower alkynyl optionally substituted with moieties selected from the group consisting of hydroxyl, amino, lower aminoalkyl, halide, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, lower alkylcarbonylamino, carboxyl, amide, hydroxyamide, —CONHCH 3 , —NHCONH 2 , —SO 2 NH 2 , —SO 2 CH 3 , —NHCOCH 3 , —NHCSNH 2 , and —NHSO 2 CH 3 ; and wherein R 10  and R 11  together with the carbon atoms to which they are attached form an aromatic N-heterocycle which is substituted or not selected from the group consisting of indole, imidazole, quinoline, isoquinoline, pyridine, triazine, pyrazine, pyrimidine, pyridazine, isoindole, pyrrole, benzimidazole, purine, pyrazole, benzopyrazole, indazole, quinoxaline, acridine, quinazoline, indolizine, carbazole and cinnoline; and salts thereof. 
       
     
     
         76 . A method according to  claim 75  wherein the compound corresponds to the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, methyl, halide, lower haloalkyl, nitrile, lower alkyl nitrile, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, lower cycloalkyl, lower cycloalkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; wherein R 2  is selected from the group consisting of carboxyl, amide, hydroxyamide, methylamide, —CH 2 N(CH 3 ) 2 , —CH 2 NR 6 R 7 , 
       
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of hydrogen and methyl; wherein one of R 4  and R 5  is hydrogen and the other is methyl; wherein R 6  and R 7  are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and butyl; wherein R 8  is selected from the group consisting of hydroxyl, amino, —N(CH 3 ) 2 , and —NHCH 3 ; and wherein R 9  is selected from the group consisting of hydrogen, halide, lower alkyl, lower alkenyl, lower alkynyl, morpholinyl, piperazinyl, lower alkyl piperazinyl, heterocycloalkyl, lower cycloalkyl, lower cycloalkenyl; and lower alkyl, lower alkenyl, and lower alkynyl optionally substituted with moieties selected from the group consisting of hydroxyl, amino, lower aminoalkyl, halide, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, lower alkylcarbonylamino, carboxyl, amide, hydroxyamide, —CONHCH 3 , —NHCONH 2 , —SO 2 NH 2 , —SO 2 CH 3 , —NHCOCH 3 , —NHCSNH 2 , and —NHSO 2 CH 3 ; and salts thereof. 
       
     
     
         77 . A method according to  claim 75  wherein the compound corresponds to the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R1 is selected from the group consisting of hydrogen, methyl, halide, nitrile, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; wherein R3 is selected from the group consisting of hydrogen and methyl; and wherein one of R4 and R5 is hydrogen and the other is methyl; and salts thereof. 
       
     
     
         78 . A method according to  claim 75 , wherein the compound corresponds to the followings chemical structure: