SecA INHIBITORS AND METHODS OF MAKING AND USING THEREOF

Abstract

Inhibitors of SecA, and methods of making and using thereof, are described herein. The compounds described herein can be used to treat or prevent microbial infections, such as bacterial infections.

1 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
         wherein
 X of Formula VI is O, S, SO, SO 2 , NR 11 , or CR 12 R 13 ; and 
 R 1 -R 13  of Formula VI are independently absent or selected from hydrogen, ethyl, n-propyl, isopropyl, n-, sec-, iso-, or t-butyl, pentyl, hexyl, heptyl, substituted or unsubstituted cyclopentanyl; substituted or unsubstituted, linear, branched, or hetero alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 14 , —CONR 14 R 14 , —OCONHR 14 , —NHCOOR 14 , —OCONR 14 R 14 , —NR 14 COOR 14 , NHCONHR 14 , —NR 14 CONHR 14 , —NHCONR 14 R 14 , —NR 14 CONR 14 R 14 , —CH 2 OH; —CHR 14 OH, —CR 14 R 14 OH, —COOR 14 ), thiol, —NH 2 , —NHR 14 , —NR 14 R 14 , —SR 14 , —SOR 14 , and —SOOR 14 , wherein R 14  of Formula VI is defined the same as R 1 -R 13  of Formula VI; 
 
       
       
         
           
           
               
               
           
         
         wherein
 X of Formula VII is O, S, SO, SO 2 , NR 9 , CR 10 R 11 ; and 
 R 1 -R 11  of Formula VII are independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , CONHR 12 , —CONR 12 R 12 , —OCONHR 12 , —NHCOOR 12 , —OCONR 12 R 12 , —NR 14 COOR 12 , NHCONHR 12 , —NR 12 CONHR 12 , —NHCONR 12 R 12 , —NR 14 CONR 12 R 12 , —CH 2 OH, —CHR 12 OH, —CR 12 R 12 OH, —COOR 12 , thiol, —NH 2 , —NHR 12 , —NR 12 R 12 , —SR 12 , —SOR 12 , and —SOOR 12 , wherein R 12  of Formula VII is defined the same as R 1 -R 11  of Formula VII; and 
 wherein the compound of Formula VII is not Rose Bengal; 
 
       
       
         
           
           
               
               
           
         
         wherein
 A and B of Formula I are independently S, SO 2 , SO, O, NR 6 , or CR 7 R 8 ; 
 W and Z of Formula I are independently N or CR 9 ; 
 X and Y of Formula I are independently S, O, or CR 10 R 11 ; and 
 R 1 -R 11  of Formula I are independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen, substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 12 , —CONR 12 R 12 , —OCONHR 12 , —NHCOOR 12 , —OCONR 12 R 12 , —NR 12 COOR 12 , NHCONHR 12 , —NR 12 CONHR 12 , —NHCONR 12 R 12 , —NR 12 CONR 12 R 12 , —CH 2 OH, —CHR 12 OH, —CR 12 R 12 OH, —COOR 12 , thiol, —NH 2 , —NHR 12 , —NR 12 R 12 , —SR 12 , —SOR 12 , and —SOOR 12 , wherein R 12  of Formula I is defined the same as R 1 -R 11  of Formula I; 
 
       
       
         
           
           
               
               
           
         
         wherein
 X of Formula II is S, SO, SO 2 , NHR 4 , O, or CR 5 R 6 ; 
 Y of Formula II is N or CR 7 ; 
 Z of Formula II is S, O, NR 8 , or CR 9 R 10 ; and 
 R 1 -R 10  of Formula II is independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 11 , —CONR 11 R 11 , —OCONHR 11 , —NHCOOR 11 , —OCONR 11 R 11 , —NR 11 COOR 11 , NHCONHR 11 , —NR 10 CONHR 11 , —NHCONR 11 R 11 , —NR 11 CONR 11 R 11 , —CH 2 OH, —CHR 11 OH, —CR 11 R 11 OH, —COOR 11 , thiol, —NH 2 , —NHR 11 , —NR 11 R 11 , —SR 11 , —SOR 11 , and —SOOR 11 , wherein R 11  of Formula II is defined the same as R 1 -R 10  of Formula II; 
 
       
       
         
           
           
               
               
           
         
         wherein
 X of Formula IV is O, S, NR 10 , or CR 11 R 12 ; 
 R 1 -R 12  of Formula IV are independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 13 , —CONR 13 R 13 , —OCONHR 13 , —NHCOOR 13 , —OCONR 13 R 13 , —NR 14 COOR 13 , NHCONHR 13 , —NR 14 CONHR 13 , —NHCONR 13 R 13 , —NR 17 CONR 13 R 13 , —CH 2 OH, —CHR 13 OH, —CR 13 R 13 OH, —COOR 13 , thiol, —NH 2 , —NHR 13 , —NR 13 R 13 , —SR 13 , —SOR 13 , and —SOOR 13 , wherein R 13  of Formula IV is defined the same as R 1 -R 12  of Formula IV; and 
 the dotted lines represent optional double bonds; 
 
       
       
         
           
           
               
               
           
         
         wherein
 X and Y of Formula V are independently O, S, NR 13 , or CR 14 R 15 ; and 
 R 1 -R 15  of Formula V are independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 16 , —CONR 16 R 16 , —OCONHR 16 , —NHCOOR 16 , —OCONR 16 R 16 , —NR 16 COOR 16 , NHCONHR 16 , —NR 16 CONHR 16 , —NHCONR 16 R 16 , —NR 16 CONR 16 R 16 , —CH 2 OH, —CHR 16 OH, —CR 16 R 16 OH, —COOR 16 , thiol, —NH 2 , —NHR 16 , —NR 16 R 16 , —SR 16 , —SOR 16 , and —SOOR 16 , wherein R 16  of Formula V is defined the same as R 1 -R 15  of Formula V; 
 
       
       
         
           
           
               
               
           
         
         wherein
 Z of Formula VIII is O, S, SO, SO 2 , NR 6 , or CR 7 R 8 ; 
 X and Y of Formula VIII are independently N, NR 9 , or CR 10 R 11 ; 
 R 1 -R 11  of Formula VIII are independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 12 , —CONR 12 R 12 , —OCONHR 12 , —NHCOOR 12 , —OCONR 12 R 12 , —NR 14 COOR 12 , NHCONHR 12 , —NR 12 CONHR 12 , —NHCONR 12 R 12 , —NR 14 CONR 12 R 12 , —CH 2 OH, —CHR 12 OH, —CR 12 R 12 OH, —COOR 12 , thiol, —NH 2 , —NHR 12 , —NR 12 R 12 , —SR 12 , —SOR 12 , and —SOOR 12 , wherein R 12  of Formula VIII is defined the same as R 1 -R 11  of Formula VIII; and 
 the dotted lines represent optional double bonds; or 
 
       
       
         
           
           
               
               
           
         
         wherein
 Z of Formulas IX and IXa is O, S, SO, SO 2 , NR 7 , or CR 8 R 9 ; 
 X and Y of Formulas IX and IXa are independently N, NR 10 , or CR 11 R 12 ; 
 R 1 -R 12  of Formulas IX and IXa are independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 13 , —CONR 13 R 13 , —OCONHR 13 , —NHCOOR 13 , —OCONR 13 R 13 , —NR 13 COOR 13 , NHCONHR 13 , —NR 13 CONHR 13 , —NHCONR 13 R 13 , —NR 13 CONR 13 R 13 , —CH 2 OH, —CHR 13 OH, —CR 13 R 13 OH, —COOR 13 , thiol, —NH 2 , —NHR 13 , —NR 13 R 13 , —SR 13 , —SOR 13 , and —SOOR 13 , wherein R 13  of Formulas IX and IXa is defined the same as R 1 -R 12  of Formulas IX and IXa. 
 
       
     
     
         2 - 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein the compound is a compound of Formula VI, wherein R 1 -R 2  are independently absent or selected from the group consisting of hydrogen; halogen; hydroxyl; ethyl, n-propyl, isopropyl, n-, sec-, iso-, or t-butyl, pentyl, hexyl, heptyl; substituted or unsubstituted cyclopentanyl; substituted or unsubstituted alkoxy; substituted or unsubstituted alkenyl, cycloalkenyl, heterocycloalkyl, and heteroaryl; wherein R 1 -R 2  are optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxyl; ethyl, n-propyl, isopropyl, n-, sec-, iso-, or t-butyl, pentyl, hexyl, or heptyl; substituted or unsubstituted cyclopentanyl; substituted or unsubstituted alkoxy; substituted or unsubstituted alkenyl, cycloalkenyl, heterocycloalkyl, heteroaryl; or R 1 -R 2  taken together is O, S, SO, SO 2 , NR 11 , or CR 12 R 13 ;
 wherein R 3 -R 13  are independently absent or selected from the group consisting of hydrogen; halogen; hydroxyl; substituted or unsubstituted alkoxy; substituted or unsubstituted alkyl; of —OR 14 ; cycloalkyl; cycloalkenyl; primary amine; secondary amine; tertiary amine; —C(O)R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , —NR 14 R 14 , —NR 14 S(O) 2 R 14 , —NR 14 C(O)R 14 , —S(O) 2 R 14 , —SR 14 , and —S(O) 2 NR 14 R 14 ; and   R 14  is independently selected from the group consisting of hydrogen, halogen, cyano, —OR 14 , alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, and heteroaryl.   
     
     
         13 . The compound of  claim 12 , wherein X is O and wherein R 3 -R 13  are independently absent or selected from the group consisting of hydrogen; halogen; hydroxyl; alkoxy; substituted or unsubstituted alkyl; primary amine, secondary amine, and tertiary amine. 
     
     
         14 . The compound of  claim 1 , wherein the compound is a compound of Formula VI, wherein the compound of Formula VI is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein the compound is a compound of Formula VII, wherein the compound of Formula VII is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . (canceled) 
     
     
         17 . A pharmaceutical composition comprising one or more compounds of  claim 1  and one or more pharmaceutically acceptable carriers. 
     
     
         18 . A method of treating an infection comprising administering or the composition of  claim 17  in an amount effective to inhibit SecA. 
     
     
         19 . The method according to  claim 18 , wherein the infection is a fungal, bacterial, or viral infection. 
     
     
         20 . The method according to  claim 19 , wherein the infection is a bacterial infection. 
     
     
         21 . The method according to  claim 18 , wherein the composition is administered by one or more routes selected from the group consisting of buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration. 
     
     
         22 . (canceled) 
     
     
         23 . A method for assessing the inhibitory effect of any one of the compounds of  claim 1  on ATPase membrane channel activities, the method comprising:
 injecting a SecA-liposome and various concentrations of the compound into the membrane of oocytes, and 
 determining the IC 50  value of the compound. 
 
     
     
         24 . The method of  claim 23 , wherein the liposome further comprises a protein selected from the group consisting of SecYEG and SecYEG/DF.YajC. 
     
     
         25 . The compound of  claim 1 , wherein the compound is a compound of Formula VI. 
     
     
         26 . The compound of  claim 1 , wherein the compound is a compound of Formula VII. 
     
     
         27 . The compound of  claim 1 , wherein the compound is a compound of Formula I. 
     
     
         28 . The compound of  claim 1 , wherein the compound is a compound of Formula II. 
     
     
         29 . The compound of  claim 1 , wherein the compound is a compound of Formula IV. 
     
     
         30 . The compound of  claim 1 , wherein the compound is a compound of Formula V. 
     
     
         31 . The compound of  claim 1 , wherein the compound is a compound of Formula VIII. 
     
     
         32 . The compound of  claim 1 , wherein the compound is a compound of Formula IX or IXa. 
     
     
         33 . The compound of  claim 1 , wherein the compound is a compound of Formula I, wherein the compound of Formula I is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 1 , wherein the compound is a compound of Formula II, wherein the compound of Formula II is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         35 . The pharmaceutical composition of  claim 17 , wherein the composition comprises one or more compounds of Formula VI and one of more compounds of Formula I. 
     
     
         36 . The pharmaceutical composition of  claim 17 , wherein the composition comprises one or more compounds of Formula VII and one of more compounds of Formula I. 
     
     
         37 . The pharmaceutical composition of  claim 17 , wherein the composition comprises one or more compounds of Formula VI and one of more compounds of Formula II. 
     
     
         38 . The pharmaceutical composition of  claim 17 , wherein the composition comprises one or more compounds of Formula VII and one of more compounds of Formula II. 
     
     
         39 . The pharmaceutical composition of  claim 17 , further comprising one or more further compounds, or a pharmaceutically acceptable salt thereof, wherein the further compounds have, independently, the following formula: 
       
         
           
           
               
               
           
         
         wherein
 X and Y of Formula III are independently N or C; 
 D and G of Formula III are independently NR 7 , CR 8 R 9 , O, or S; 
 A, B, E, and F of Formula III are independently N or CR 10 ; 
 L and M of Formula III are independently S, SO, SO 2 , O, NR 11 , or CR 12 R 13    
 J of Formula III is O, S, SO, SO 2 , NR 14 , or CR 15 R 16 ; and 
 R 1 -R 16  of Formula III are independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 17 , —CONR 17 R 17 , —OCONHR 17 , —NHCOOR 17 , —OCONR 17 R 17 , —NR 14 COOR 17 , NHCONHR 17 ; —NR 14 CONHR 17 , —NHCONR 17 R 17 , —NR 17 CONR 17 R 17 , —CH 2 OH, —CHR 17 OH, —CR 17 R 17 OH, —COOR 17 , thiol, —NH 2 , —NHR 17 , —NR 17 R 17 , —SR 17 , —SOR 17 , and —SOOR 17 , wherein R 17  of Formula III is defined the same as R 1 -R 16  of Formula III; or 
 
       
       
         
           
           
               
               
           
         
         wherein
 Z and W of Formula X or Xa are O, S, SO, SO 2 , NR 5 , or CR 6 R 7 ; 
 X and Y of Formula X or Xa are independently N, NR 8 , or CR 9 R 10 ; 
 Cy of Formula X or Xa is substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; and 
 R 1 -R 10  of Formula X or Xa are independently absent or selected from hydrogen, substituted or unsubstituted, linear, branched, hetero, or cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted aryl or heteroaryl; halogen; substituted or unsubstituted alkoxy; hydroxy, cyano, formyl, acyl, carboxylic acid, carboxylate, —CONH 2 , —CONHR 11 , —CONR 11 R 11 , —OCONHR 11 , —NHCOOR 11 , —OCONR 11 R 11 , —NR 14 COOR 11 , NHCONHR 11 , —NR 11 CONHR 11 , —NHCONR 11 R 11 , —NR 14 CONR 11 R 11 , —CH 2 OH, —CHR 11 OH, —CR 11 R 11 OH, —COOR 11 , thiol, —NH 2 , —NHR 11 , —NR 11 R 11 , —SR 11 , —SOR 11 , and —SOOR 11 , wherein R 11  of Formula X or Xa is defined the same as R 1 -R 10  of Formula X or Xa. 
 
       
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula I and one of more compounds of Formula III. 
     
     
         41 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula I and one of more compounds of Formula X or Xa. 
     
     
         42 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VI and one of more compounds of Formula III. 
     
     
         43 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VI and one of more compounds of Formula X or Xa. 
     
     
         44 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VII and one of more compounds of Formula III. 
     
     
         45 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VII and one of more compounds of Formula X or Xa. 
     
     
         46 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VI, one or more compounds of Formula I, and one of more compounds of Formula III. 
     
     
         47 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VII, one or more compounds of Formula I, and one of more compounds of Formula III. 
     
     
         48 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VI, one or more compounds of Formula I, and one of more compounds of Formula X or Xa. 
     
     
         49 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VII, one or more compounds of Formula I, and one of more compounds of Formula X or Xa. 
     
     
         50 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula II and one of more compounds of Formula III. 
     
     
         51 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula II and one of more compounds of Formula X or Xa. 
     
     
         52 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VI, one or more compounds of Formula II, and one of more compounds of Formula III. 
     
     
         53 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VII, one or more compounds of Formula II, and one of more compounds of Formula III. 
     
     
         54 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VI, one or more compounds of Formula II, and one of more compounds of Formula X or Xa. 
     
     
         55 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more compounds of Formula VII, one or more compounds of Formula II, and one of more compounds of Formula X or Xa.