4-substituted tetracyclines and methods of use thereof

A compound of formula (I):

• wherein:
• R2′ and R2 are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R10, R11 and R12 are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a prodrug moiety;
• R3 is hydrogen, or a prodrug moiety;
• R4 is N—OR4a;
• R4a is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
• R5 and R5′ are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
• R6 and R6′ are each independently hydrogen, methylene, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• R7 is hydrogen or dimethylamino;
• R8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH2)0-3(NR8C)0-1C (═E′)ER8a;
• R9 is hydrogen or aminoalkyl;
• R8a, R8b, R8c, R8d, R8e and R8f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• E is CR8dR8e, S, NR8b or O;
• E′ is O, NR8f, or S;
• X is CHC(R13Y′Y), C═CR13Y, CR6′R6, S, NR6, O;
• Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyan, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• or a pharmaceutically acceptable salt, ester or enantiomer thereof.