High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds

Abstract

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) of antimicrobials and antimicrobial-related compounds, which are capable of crossing biological barriers with high penetration efficiency. The HPCs/HPPs are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPCs/HPPs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

What is claimed is: 
     
         1 . A high penetration compound having the following chemical structure: 
       
         
           
           
               
               
           
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof;
 wherein F has a structure selected from Structure F-1, Structure FP-1, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11, Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21, Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31, Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure FP-39, Structure FP-40, Structure FP-41, Structure FP-42, Structure FP-43, Structure FP-44, Structure FP-45, Structure FP-46, Structure FP-47, Structure FP-48, Structure FP-49, Structure FP-50, Structure FP-51, Structure FP-52, Structure FP-53, Structure FP-54, Structure FP-55, Structure FP-56, Structure FP-57, Structure FP-58, Structure FP-59, Structure FP-60, Structure FP-61, Structure FP-62, Structure FP-63, Structure FP-64, Structure FP-65, Structure FP-66, Structure FP-67, Structure FP-68, Structure FP-69, Structure FP-70, Structure FP-71, Structure FP-72, Structure FP-73, Structure FP-74, Structure FP-75, Structure FP-76, Structure FP-77, Structure FP-78, Structure FP-79, Structure FP-80, Structure FP-81, Structure FP-82, Structure FP-83, Structure FP-84, Structure FP-85, Structure FP-86, Structure FI-1, Structure FI-2, Structure FI-3; 
 W is selected from Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5 Structure W-7, Structure W-8, Structure W-10, Structure W-13, and Structure W-14; 
 Z is selected from CH 2 , S, SO, SO 2 , NH, NR 6 , CHCH 3 , CHCH 2 CH 3 , CR 6 , R 6 , —C(═O)—, and O; 
 AA is an amino acid; 
 m and n are each independently selected from 0 and integers 1 through 20; 
 R is selected from nothing, H, CH 2 C(═O)OR 6 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH 2  in R may be further replaced with O, S, P, NR 6 , or any other pharmaceutically acceptable groups; 
 R 1 -R 3  are each independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues; 
 R 5  and R 35  are independently selected from H, C(═O)NH 2 , CH 2 CH 2 OR 6 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 2 CH 3 ) 2 , Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, —C(═O)—W, L 1 -L 4 -L 2 -W, and W; 
 R 6 , R 36  and R 46  are independently selected from H, F, Cl, Br, I, Na + , K + , C(═O)R 5 , 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1H-inden-5-yl, 4-hydroxy-1,5-naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, —C(═O)—W, -L 1 -L 4 -L 2 -W, and W; 
 R 7  and R 37  are independently selected from H, F, Cl, Br, I, CH 3 NHC(═O)CH 2 CH(NHR 8 )C(═O), R 5 N═C(NHR 6 )NHC(═O)—, C(═O)CH 3 , C(═O)R 6 , PO(OR 5 )OR 6 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, L 1 -L 4 -L 2 -W, and C—(═O)—W; 
 R 8  and R 35  are independently selected from H, F, Cl, Br, I, CH 3 , C 2 H 5 , CF 3 , CH 2 CH 2 F, CH 2 CH 2 Cl, CH 2 CH 2 Br, CH 2 CH 21 , CH 2 CHF 2 , CH 2 CF 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 21 , CH 2 NR 6 R 7 , CH(NHR 7 )CH 2 C(═O)NH 2 , C 3 H 7 , C 4 H 9 , C 5 H 11 , R 6 , C(═O)R 6 , C(═O)NH 2 , CH 2 C(═O)NH 2 , CH 2 OC(═O)NH 2 , PO(OR 5 )OR 6 , C(CH 3 ) 2 C(═O)OR 6 , CH(CH 3 )C(═O)OR 6 , CH 2 C(═O)OR 6 , C(═O)—W, L 1 -L 4 -L 2 -W, W, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide and substituted and unsubstituted alkylcarbonyl; 
 R 11 -R 14  are each independently selected from substituted and unsubstituted alkylene; 
 X is selected from nothing, C(═O), OC(═O), CH 2 , CH, S, NH, NR 6 , and O; 
 X 2  is selected from nothing, H, CH 2 (CH 2 ) n OR 8 , Cl, F, Br, I, NO 2 , CN, CF 3 , C 2 F 5 , C 3 F 7 , OCF 3 , OC 2 F 5 , NH 2 , NHR 6 , CH 3 , C 2 H 5 , R 6 , C(═O)NH 2 , CH 2 OC(═O)NH 2 , CH 2 C(═O)OR 5 , CH 2 (CH 2 ) n N(CH 3 ) 2 , CH 2 (CH 2 ) n SO 3 R 5 , substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, and substituted and unsubstituted alkyloxyl; 
 X 3  is selected from nothing, H, N 3 , SO 3 W, F, Cl, Br, OH, OCH 3 , OR 6 , CH 3 , R 6 , C(═O)OW, OW, L 1 -L 4 -L 2 -W, and I; 
 X 4  is selected from nothing, N, CH, and CY 1 ; 
 X 5  and X 35  are independently selected from nothing, C(═O), OC(═O), CH 2 , CH, S, O and NR 5 ; 
 X 6 , X 36  and X 46  are independently selected from nothing, C(═O), OC(═O), CH 2 , CH, S, O and NR 5 ; 
 X 7  is selected from nothing, C(═O), OC(═O), CH 2 , CH, S, O and NR 5 . 
 Y 1 , Y 31 , Y 2 , Y 32 , Y 3 , and Y 4  are independently selected from H, OH, OW, OC(═O)W, L 1 -L 4 -L 2 -W, OC(═O)CH 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , R 6 , SO 3 R 6 , CH 2 OR 6 , CH 2 OC(═O)R 6 , CH 2 C(═O)OR 8 , OCH 3 , OC 2 H 5 , OR 6 , CH 3 SO 2 , R 6 SO 2 , CH 3 SO 3 , R 6 SO 3 , NO 2 , CN, CF 3 , OCF 3 , CH 2 (CH 2 ) n NR 5 R 6 , CH 2 (CH 2 ) n OR 6 , CH(C(═O)NH 2 )NHR 6 , CH 2 C(═O)NH 2 , F, Br, I, Cl, CH═CHC(═O)NHCH 2 C(═O)OW, CH═CHC(═O)NHCH 2 L 1 -L 4 -L 2 -W, NR 8 C(═O)R 5 , SO 2 NR 5 R 8 , C(═O)R 5 , SR 5 , substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide and substituted and unsubstituted alkylcarbonyl; 
 L 1  and L 31  are independently selected from nothing, O, S, —O-L 3 -, —S-L 3 -, —N(L 3 )-, —N(L 3 )-CH 2 —O, —N(L 3 )-CH 2 —N(L 5 )-, —O—CH 2 —O—, —O—CH(L 3 )-O, and —S—CH(L 3 )-O—; 
 L 2  and L 32  are independently is selected from nothing, O, S, —O-L 3 -, —S-L 3 -, —N(L 3 )-, —N(L 3 )-CH 2 —O, —N(L 3 )-CH 2 —N(L 5 )-, —O—CH 2 —O—, —O—CH(L 3 )-O, —S—CH(L 3 )-O—, —O-L 3 -, —N-L 3 -, —S-L 3 -, —N(L 3 )-L 5 - and L 3 ; 
 L 4  and L 34  are independently is selected from C═O, C═S, 
 
       
         
           
           
               
               
           
         
         for each L 1 , L 31 , L 2 , L 32 , L 4 , and L 34 , L 3  and L 5  are independently selected from nothing, H, CH 2 C(═O)OL 6 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide; 
         L 6  is independently selected from H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, CH═CH, C≡C, aryl, heteroaryl, or cyclic groups; 
         L 7  is independently selected from H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL 6 , CH═CH, C≡C, CHL6, aryl, heteroaryl, or cyclic groups; and 
         HA is selected from nothing, hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, and pamoic acid. 
       
     
     
         2 . The high penetration compound according to  claim 1 , wherein:
 -L 1 -L 4 -L 2 - and -L 31 -L 34 -L 32 - are independently selected from —O—, —X—, —O—X—, —N—X—, —S—X—, —X 5 —, —O—X 5 —, —N—X 5 —, —S—X 5 —, —O—X 7 —, —O—C(═O)—, —NH—C(═O)—, —C(═O)—, —C(═O)—O—, —C(═O)—N—, and C(═O)—X—;   X is selected from nothing, C(═O), OC(═O), CH 2 , CH, S, NH, NR 6 , and O;   X 6 , X 36  and X 46  are independently selected from nothing, C(═O), C(═S), OC(═O), CH 2 , CH, S, O and NR 5 ; and   X 7  is selected from nothing, C(═O), C(═S), OC(═O), CH 2 , CH, S, O and NRS.   
     
     
         3 . The high penetration compound according to  claim 1 , wherein:
 m=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   R 1  is selected from H, C 1 -C 20  alkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, and heteroaryl;   R 2  is selected from H, C 1 -C 20  alkyl, C 1 -C 20  alkyloxy, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, and heteroaryl residues;   R 3  is selected from H, C 1 -C 20  alkyl, C 1 -C 20  alkyloxy, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl and heteroaryl residues;   R 5  and R 35  are independently selected from H, —C(═O)NH 2 , CH 2 CH 2 OR 6 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 OR 6 , Cl, F, Br, I, C 1 -C 20  alkyl, C 1 -C 20  cycloalkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  cycloalkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  cycloalkenyl, C 1 -C 20  cycloalkynyl, C 1 -C 20  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 6 , R 36  and R 46  are independently selected from H, F, Cl, Br, I, Na*, K*, C(═O)R 5 , 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1H-inden-5-yl, 4-hydroxy-1,5-naphthyridin-3-yl, C 1 -C 12  alkyl, C 1 -C 12  cycloalkyl, C 1 -C 12  alkyloxyl, C 1 -C 12  cycloalkyloxyl, C 1 -C 12  alkenyl, C 1 -C 12  cycloalkenyl, C 1 -C 12  cycloalkynyl, C 1 -C 12  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 7  and R 37  are independently selected from H, F, Cl, Br, I, CH 3 NHC(═O)CH 2 CH(NHR 8 )C(═O), R 5 N═C(NHR 6 )NHC(═O)—, C(═O)CH 3 , C(═O)R 6 , PO(OR 5 )OR 6 , C 1 -C 20  alkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 8  and R 35  are independently selected from H, F, Cl, Br, I, CH 3 , C 2 H 5 , CF 3 , CH 2 CH 2 F, CH 2 CH 2 Cl, CH 2 CH 2 Br, CH 2 CH 21 , CH 2 CHF 2 , CH 2 CF 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 21 , CH 2 NR 6 R 7 , CH(NHR 7 )CH 2 C(═O)NH 2 , C 3 H 7 , C 4 H 9 , C 5 H 11 , R 6 , C(═O)R 6 , C(═O)NH 2 , CH 2 C(═O)NH 2 , CH 2 OC(═O)NH 2 , PO(OR 5 )OR 6 , C(CH 3 ) 2 C(═O)OR 6 , CH(CH 3 )C(═O)OR 6 , CH 2 C(═O)OR 6 , C(═O)—W;   X 2  is selected from nothing, H, CH 2 (CH 2 ) n OR 8 , Cl, F, Br, I, NO 2 , CN, CF 3 , C 2 F 5 , C 3 F 7 , OCF 3 , OC 2 F 5 , NH 2 , NHR 6 , CH 3 , C 2 H 5 , R 6 , C(═O)NH 2 , CH 2 OC(═O)NH 2 , CH 2 C(═O)OR 5 , CH 2 (CH 2 ) n N(CH 3 ) 2 , CH 2 (CH 2 ) n SO 3 R 5 , C 1-8  alkyl, C 1-8  alkylthio, C 1-8  alkylamino, and C 1-8  alkyloxyl;   X 3  is selected from H, N 3 , SO 3 W, F, Cl, Br, OH, OCH 3 , OR 6 , CH 3 , R 6 , C(═O)OW, OW, and I;   X 4  is selected from nothing, N, CH, and CY 1 ;   X 5  and X 35  are independently selected from nothing, C(═O), C(═S), OC(═O), CH 2 , CH, S, O and NR 5 ; and   each Y 1 , Y 31 , Y 2 , Y 32 , Y 3 , and Y 4  are independently selected from H, OH, OW, OC(═O)W, OC(═O)CH 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , SO 3 R 6 , CH 2 OR 6 , CH 2 OC(═O)R 6 , CH 2 C(═O)OR 8 , OCH 3 , OC 2 H 5 , CH 3 SO 2 , R 6 SO 2 , R 6 SO 3 OR 6 , CH 3 SO 3 , R 6 SO 3 , NO 2 , CN, CF 3 , OCF 3 , CH═CHC(═O)NHCH 2 C(═O)OW, CH 2 (CH 2 ) n NR 5 R 6 , CH 2 (CH 2 ) n OR 6 , CH(C(═O)NH 2 )NHR 6 , CH 2 C(═O)NH 2 , F, Br, I, and C.   
     
     
         4 . The high penetration compound according to  claim 1 , wherein:
 -L 1 -L 4 -L 2 - and -L 31 -L 34 -L 32 - are independently selected from —O—, —X—, —O—X—, —N—X—, —S—X—, —X 5 —, —O—X 5 —, —N—X 5 —, —S—X 5 —, —O—X 7 —, —O—C(═O)—, —NH—C(═O)—, —C(═O)—, —C(═O)—O—, —C(═O)—N—, and C(═O)—X—;   X is selected from nothing, C(═O), OC(═O), CH 2 , CH, S, NH, NR 6 , and O;   X 6 , X 36  and X 46  are independently selected from nothing, C(═O), C(═S), OC(═O), CH 2 , CH, S, O and NR 5 ; and   X 7  is selected from nothing, C(═O), C(═S), OC(═O), CH 2 , CH, S, O and NR 5 ;   m=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   R 1  is selected from H, C 1 -C 20  alkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, and heteroaryl;   R 2  is selected from H, C 1 -C 20  alkyl, C 1 -C 20  alkyloxy, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, and heteroaryl residues;   R 3  is selected from H, C 1 -C 20  alkyl, C 1 -C 20  alkyloxy, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl and heteroaryl residues;   R 5  and R 35  are independently selected from H, —C(═O)NH 2 , CH 2 CH 2 OR 6 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 OR 6 , Cl, F, Br, I, C 1 -C 20  alkyl, C 1 -C 20  cycloalkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  cycloalkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  cycloalkenyl, C 1 -C 20  cycloalkynyl, C 1 -C 20  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 6 , R 36  and R 46  are independently selected from H, F, Cl, Br, I, Na*, K*, C(═O)R 5 , 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1H-inden-5-yl, 4-hydroxy-1,5-naphthyridin-3-yl, C 1 -C 12  alkyl, C 1 -C 12  cycloalkyl, C 1 -C 12  alkyloxyl, C 1 -C 12  cycloalkyloxyl, C 1 -C 12  alkenyl, C 1 -C 12  cycloalkenyl, C 1 -C 12  cycloalkynyl, C 1 -C 12  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 7  and R 37  are independently selected from H, F, Cl, Br, I, CH 3 NHC(═O)CH 2 CH(NHR 8 )C(═O), R 5 N═C(NHR 6 )NHC(═O)—, C(═O)CH 3 , C(═O)R 6 , PO(OR 5 )OR 6 , C 1 -C 20  alkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 8  and R 38  are independently selected from H, F, Cl, Br, I, CH 3 , C 2 H 5 , CF 3 , CH 2 CH 2 F, CH 2 CH 2 Cl, CH 2 CH 2 Br, CH 2 CH 21 , CH 2 CHF 2 , CH 2 CF 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 21 , CH 2 NR 6 R 7 , CH(NHR 7 )CH 2 C(═O)NH 2 , C 3 H 7 , C 4 H 9 , C 5 H 11 , R 6 , C(═O)R 6 , C(═O)NH 2 , CH 2 C(═O)NH 2 , CH 2 OC(═O)NH 2 , PO(OR 5 )OR 6 , C(CH 3 ) 2 C(═O)OR 6 , CH(CH 3 )C(═O)OR 6 , CH 2 C(═O)OR 6 , C(═O)—W;   X 2  is selected from nothing, H, CH 2 (CH 2 ) n OR 8 , Cl, F, Br, I, NO 2 , CN, CF 3 , C 2 F 5 , C 3 F 7 , OCF 3 , OC 2 F 5 , NH 2 , NHR 6 , CH 3 , C 2 H 5 , R 6 , C(═O)NH 2 , CH 2 OC(═O)NH 2 , CH 2 C(═O)OR 5 , CH 2 (CH 2 ) n N(CH 3 ) 2 , CH 2 (CH 2 ) n SO 3 R 5 , C 1-8  alkyl, C 1-8  alkylthio, C 1-8  alkylamino, and C 1-8 alkyloxyl;   X 3  is selected from H, N 3 , SO 3 W, F, Cl, Br, OH, OCH 3 , OR 6 , CH 3 , R 6 , C(═O)OW, OW, and I;   X 4  is selected from nothing, N, CH, and CY 1 ;   X 5  and X 35  are independently selected from nothing, C(═O), C(═S), OC(═O), CH 2 , CH, S, O and NR 5 ; and   each Y 1 , Y 31 , Y 2 , Y 32 , Y 3 , and Y 4  are independently selected from H, OH, OW, OC(═O)W, OC(═O)CH 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , SO 3 R 6 , CH 2 OR 6 , CH 2 OC(═O)R 6 , CH 2 C(═O)OR 8 , OCH 3 , OC 2 H 5 , CH 3 SO 2 , R 6 SO 2 , R 6 SO 3 OR 6 , CH 3 SO 3 , R 6 SO 3 , NO 2 , CN, CF 3 , OCF 3 , CH═CHC(═O)NHCH 2 C(═O)OW, CH 2 (CH 2 ) n NR 5 R 6 , CH 2 (CH 2 ) n OR 6 , CH(C(═O)NH 2 )NHR 6 , CH 2 C(═O)NH 2 , F, Br, I, and Cl.   
     
     
         5 . The high penetration compound according to  claim 1 , having a structure selected from Structure P-1, Structure P-3, Structure P-4, Structure P-5, Structure P-6, Structure P-8, Structure P-9, Structure P-10, Structure P-11, Structure P-12, Structure P-13, Structure P-14, Structure P-15, Structure P-16, Structure P-17, Structure P-18, Structure P-19, Structure P-20, Structure P-21, Structure P-22, Structure P-23, Structure P-24, Structure P-25, Structure P-26, Structure P-27, Structure P-28, Structure P-29, Structure P-30, Structure P-31, Structure P-32, Structure P-33, Structure P-34, Structure P-35, Structure P-36, Structure P-37, Structure P-38, Structure P-39, Structure P-40, Structure P-41, Structure P-42, Structure P-43, Structure P-44, Structure P-45, Structure P-46, Structure P-47, Structure P-48, Structure P-49, Structure P-50, Structure P-51, Structure P-52, Structure P-53, Structure P-54, Structure P-55, Structure P-56, Structure P-57, Structure P-58, Structure P-59, Structure P-60, Structure P-61, Structure P-62, Structure P-63, Structure P-64, Structure P-65, Structure P-66, Structure P-67, Structure P-68, Structure P-69, Structure P-70, Structure P-71, Structure P-72, Structure P-73, Structure P-74, Structure P-75, Structure P-76, Structure P-77, Structure P-78, Structure P-79, Structure P-80, Structure P-81, Structure P-82, Structure P-83, Structure P-84, Structure P-85, Structure P-86, Structure I-1, Structure I-2, and Structure I-3, including stereoisomers and pharmaceutically acceptable salts thereof, wherein m, n, R 1 , R 2 , R 5 , R 35 , R 6 , R 36 , R 46 , R 7 , R 8 , R 38 , T, W, X, X 2 , X 4 , X 5 , X 35 , X 6 , X 36 , X 46 , X 7 , Y 1 , Y 2 , Y 31 , Y 32 , Y 3 , Y 4 , Z, AA, HA, R, R s , and R 11 -R 16  are defined the same as in  claim 1 . 
     
     
         6 . The high penetration compound according to  claim 5 , wherein:
 m=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   R 1  is selected from H, C 1 -C 20  alkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, and heteroaryl;   R 2  is selected from H, C 1 -C 20  alkyl, C 1 -C 20  alkyloxy, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, and heteroaryl residues;   R 5  and R 35  are independently selected from H, —C(═O)NH 2 , CH 2 CH 2 OR 6 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 OR 6 , Cl, F, Br, I, C 1 -C 20  alkyl, C 1 -C 20  cycloalkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  cycloalkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  cycloalkenyl, C 1 -C 20  cycloalkynyl, C 1 -C 20  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 6 , R 36  and R 46  are independently selected from H, F, Cl, Br, I, Na*, K*, C(═O)R 5 , 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1H-inden-5-yl, 4-hydroxy-1,5-naphthyridin-3-yl, C 1 -C 12  alkyl, C 1 -C 12  cycloalkyl, C 1 -C 12  alkyloxyl, C 1 -C 12  cycloalkyloxyl, C 1 -C 12  alkenyl, C 1 -C 12  cycloalkenyl, C 1 -C 12  cycloalkynyl, C 1 -C 12  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 7  is selected from H, F, Cl, Br, I, CH 3 NHC(═O)CH 2 CH(NHR 8 )C(═O), R 5 N═C(NHR 6 )NHC(═O)—, C(═O)CH 3 , C(═O)R 6 , PO(OR 5 )OR 6 , C 1 -C 20  alkyl, C 1 -C 20  alkyloxyl, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, aryl, heteroaryl, C(═O)—W, and W;   R 8  and R 38  are independently selected from H, F, Cl, Br, I, CH 3 , C 2 H 5 , CF 3 , CH 2 CH 2 F, CH 2 CH 2 Cl, CH 2 CH 2 Br, CH 2 CH 21 , CH 2 CHF 2 , CH 2 CF 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 21 , CH 2 NR 6 R 7 , CH(NHR 7 )CH 2 C(═O)NH 2 , C 3 H 7 , C 4 H 9 , C 5 H 11 , R 6 , C(═O)R 6 , C(═O)NH 2 , CH 2 C(═O)NH 2 , CH 2 OC(═O)NH 2 , PO(OR 5 )OR 6 , C(CH 3 ) 2 C(═O)OR 6 , CH(CH 3 )C(═O)OR 6 , CH 2 C(═O)OR 6 , C(═O)—W;   X 2  is selected from nothing, H, CH 2 (CH 2 ) n OR 8 , Cl, F, Br, I, NO 2 , CN, CF 3 , C 2 F 5 , C 3 F 7 , OCF 3 , OC 2 F 5 , NH 2 , NHR 6 , CH 3 , C 2 H 5 , R 6 , C(═O)NH 2 , CH 2 OC(═O)NH 2 , CH 2 C(═O)OR 5 , CH 2 (CH 2 ) n N(CH 3 ) 2 , CH 2 (CH 2 ) n SO 3 R 5 , C 1-8  alkyl, C 1-8  alkylthio, C 1-8  alkylamino, and C 1-8 alkyloxyl;   X 3  is selected from H, N 3 , SO 3 W, F, Cl, Br, OH, OCH 3 , OR 6 , CH 3 , R 6 , C(═O)OW, OW, and I;   X 4  is selected from nothing, N, CH, and CY 1 ;   X 5  and X 35  are independently selected from nothing, C(═O), C(═S), OC(═O), CH 2 , CH, S, O and NR 5 ; and   each Y 1 , Y 31 , Y 2 , Y 32 , Y 3 , and Y 4  are independently selected from H, OH, OW, OC(═O)W, OC(═O)CH 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , SO 3 R 6 , CH 2 OR 6 , CH 2 OC(═O)R 6 , CH 2 C(═O)OR 8 , OCH 3 , OC 2 H 5 , CH 3 SO 2 , R 6 SO 2 , R 6 SO 3 OR 6 , CH 3 SO 3 , R 6 SO 3 , NO 2 , CN, CF 3 , OCF 3 , CH═CHC(═O)NHCH 2 C(═O)OW, CH 2 (CH 2 ) n NR 5 R 6 , CH 2 (CH 2 ) n OR 6 , CH(C(═O)NH 2 )NHR 6 , CH 2 C(═O)NH 2 , F, Br, I, and Cl.   
     
     
         7 . A high penetration compound selected from:
 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl ester;   allylmercaptomethylpenicillinic acid 2-dimethylaminoethyl ester;   6-(2,6-dimethoxybenzamido)penicillinic acid 2-dipropylaminoethyl ester;   6-(5-methyl-3-phenyl-2-isoxazoline-4-carboxamido)penicillinic acid 4-piperidineethyl ester;   6-[3-(o-chlorophenyl)-5-methyl-4-isoxazolecarboxamido]penicillinic acid 3-piperidineethyl ester;   6-[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarboxamido]penicillinic acid 1-piperidineethyl ester;   6-[D(−)-α-aminophenylacetamidopenicillinic acid ethyl ester;   D-α-[(imidazolidin-2-on-1-yl)carbonylamino]benzylpenicillin 2-pyrrolidinemethyl ester;   6R-[2-[3-(methylsulfonyl)-2-oxo-1-imidazolidinecarboxamido]-2-phenylacetamido]penicillinic acid 1-pyrrolidineethyl ester;   6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-a-phenylacetamidopenicillinic acid 2-diethylaminoethyl ester;   7-(2-thienylacetamido)cephalosporanic acid 2-diethylaminoethyl ester;   7-[(hydroxyphenylacetyl)amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   3-[[(aminocarbonyl)oxy]methyl]-7-[[2-furanyl(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   7-[[[2-(acetylaminomethyl)phenyl]acetyl]amino]-3-[[[1-(ethoxylcarbonylmethyl)-1H-tetrazol-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   7-[(acetylaminophenylacetyl)amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   3-[(acetyloxy)methyl]-7-[[(2-acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   7-[[(2-acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-acetoxyphenyl)acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   7-[2-(2-acetylamino-4-thiazolyl)-2-((Z)-methoxyimino)acetamido]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester;   7-[2-(2-acetylamino-4-thiazolyl)-2-((Z)-ethoxycarbonylmethoxy)imino]acetamido]-3-(vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl este;   4-(4-dimethylaminobutyryl)amidobenzenesulfonamide (DMAB-sulfanilamide);   6-oxo-3-(2-[4-(N-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1,4-dienecarboxylic acid N,N-diethyaminopropyl ester (sulfasalazine-DEPE);   1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-quinoline-3-carboxylic acid butyl ester (ciprofloxacin-BE); and   1-ethyl-7-methyl-4-oxo-[, 8]naphthyridine-3-carboxylic acid N,N-diethylaminoethyl ester (nalidixic acid-DEE); and   pharmaceutical acceptable salts thereof.   
     
     
         8 . The high penetration compound of  claim 7 , wherein the pharmaceutically acceptable salt is hydrochloride salt or hydrobromide salt. 
     
     
         9 . A pharmaceutical composition comprising a high penetration compound according to  claim 7  and a pharmaceutically acceptable carrier. 
     
     
         10 . A pharmaceutical composition comprising a high penetration compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein the pharmaceutically acceptable carrier comprises a polar solvent. 
     
     
         12 . The pharmaceutical composition according to  claim 10 , wherein the pharmaceutically acceptable carrier is selected from alcohol, acetone, ester, water, aqueous solution, and combinations thereof. 
     
     
         13 . A method for treating a condition in a biological subject, comprising administrating to the biological subject a therapeutically effective amount of a high penetration compound according to  claim 1 , or a pharmaceutically acceptable salt or composition thereof. 
     
     
         14 . The method according to  claim 13 , wherein the condition is selected from pain, injuries, and microorganism related conditions. 
     
     
         15 . The method according to  claim 14 , wherein the microorganism related condition is selected from bacteria-related conditions, protozoa-related conditions, fungi-related conditions, and conditions caused by virus. 
     
     
         16 . The method according to  claim 15 , wherein the bacteria-related condition is selected from infections, plague, bubonic plague and pneumonic plague, anthrax, cutaneous anthrax, pulmonary anthrax and gastrointestinal antrax, lyme diseases, brucellosis, whooping cough, acute enteritis, respiratory infection, psittacosis, nongonococcal urethritis, trachoma, inclusion conjunctivitis of the newborn, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, diarrhea, meningitis in infants, hemorrhagic colitis, hemolytic-uremic syndrome, tularemia, pneumonia, bronchitis, peptic ulcer, legionnaire's disease, Pontiac fever, leptospirosis, listeriosis, leprosy, turberculosis,  mycoplasma  pneumonia, gonorrhea, ophthalmia neonatorum, septic arthritis, meningococcal disease, waterhouse-friderichsen syndrome, Rocky mountain spotted fever, typhoid fever type salmonellosis, salmonellosis with gastroenteritis and enterocolitis, bacillary dysentery/shigellosis, cystitis, meningitis and septicemia, endometritis, otitis media, sinusitis, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, rheumatic fever, impetigo, erysipelas, puerperal fever, and cholera. 
     
     
         17 . The method according to  claim 16 , wherein the infection condition is selected from an infection condition in an organ selected from liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani, respiratory infections, upper respiratory tract, urinary tract, nosocomial infections,  pseudomonas  infection, coagulase-positive staphylococcal infections, skin infection, toxinoses, acute infective endocarditis, septicemia, necrotizing pneumonia, infections of implanted prostheses, and opportunistic infections with septicemia and pneumonia. 
     
     
         18 . The method according to  claim 15 , wherein the protozoa-related condition is selected from malaria, sleeping sickness, and toxoplasmosis. 
     
     
         19 . The method according to  claim 15 , wherein the fungi-related condition is selected from aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis. 
     
     
         20 . The method according to  claim 15 , wherein the virus-related condition is selected from influenza, yellow fever and AIDS.