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 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 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.

1 . A high penetration composition of an antimicrobial or an antimicrobial-related compound comprising
 a) a functional unit;   b) a linker   c) a transportational unit;   wherein the functional unit is covalently linked to the transportational unit via the linker;   wherein the functional unit comprises a moiety of the antimicrobial or the antimicrobial-related compound;   wherein the transportational unit comprises a protonatable amine group; and   wherein the linker comprises a chemical bond that is capable of being cleaved after the high penetration composition penetrates across a biological barrier.   
   
   
       2 . The high penetration composition according to  claim 1 , wherein the chemical bond is selected from the group consisting of a covalent chemical bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond. 
   
   
       3 . The high penetration composition according to  claim 1 , wherein upon cleavage of the cleavable bond, the moiety of the antimicrobial or the antimicrobial-related compound is converted to the antimicrobial or the antimicrobial-related compound. 
   
   
       4 . The high penetration composition according to  claim 1 , wherein the functional unit comprises a lipophilic derivative of a moiety of the beta-lactam antibiotics or the beta-lactam antibiotics-related compound. 
   
   
       5 . The high penetration composition according to  claim 4 , wherein the lipophilic derivative is selected from the group consisting of carbonate, ester, amide, carbamate, N-mannich base, ether, thioether, thioester, phosphate, oxime and imine. 
   
   
       6 . The high penetration composition according to  claim 1  wherein the beta-lactam antibiotics or the beta-lactam antibiotics-related compound is selected from the group consisting of beta-lactam antibiotics, beta-lactam antibiotics metabolites, and agents that can be metabolized into a beta-lactam antibiotics or a beta-lactam antibiotics metabolite, and analogs thereof. 
   
   
       7 . The high penetration composition according to  claim 1 , wherein the protonatable amine group is selected from the group consisting of a substituted and unsubstituted primary amine group, a substituted and unsubstituted secondary amine group, and a substituted and unsubstituted tertiary amine group. 
   
   
       8 . The high penetration composition according to  claim 7 , wherein the protonatable amine group is selected from the group consisting of Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
       HA is selected from the group consisting of 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; 
       R is selected from the group consisting of nothing, H, CH 2 COOR 6 , substituted and unsubstituted alkyl, 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 2  are independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues; 
       R 5  is selected from the group consisting of H, CONH 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 alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, COW, L 1 -L 4 -L 2 -W, and W; 
       R 6  is selected from the group consisting of H, F, Cl, Br, I, Na + , K + , COR 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 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 11 -R 16  are independently selected from the group consisting of nothing, H, CH 2 COOR 11 , substituted and unsubstituted alkyl, 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; 
       L 1  is selected from the group consisting of nothing, O, S, —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  is selected from the group consisting of nothing, O, S, —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  is selected from the group consisting of C═O, C═S, 
     
     
       
         
         
             
             
         
       
       for each L 1 , L 2 , and L 4 , L 3  and L 5  are independently selected from the group consisting of 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, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NL 3 , or any other pharmaceutically acceptable groups; 
       L 6  is independently selected from the group consisting of 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, CHL 6 , CL 6 L 7 , aryl, heteroaryl, or cyclic groups; and 
       L 7  is independently selected from the group consisting of 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, CHL 6 , CL 6 L 7 , aryl, heteroaryl, or cyclic groups; and 
       W is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17, Structure W-18 and Structure Wa: 
     
     
       
         
         
             
             
         
       
     
   
   
       9 . A high penetration composition having the following chemical structure: 
     
       
         
         
             
             
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
       F comprises a moiety of a beta-lactam antibiotics or a beta-lactam antibiotics-related compound, having a structure selected from the group consisting of Structure F-1, Structure FP-1, Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, 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, Structure FI-4, Structure FI-5, Structure FI-6, Structure FI-7, Structure FI-8, Structure FI-9, Structure FI-10, Structure FI-11, Structure FI-12, Structure FI-13, Structure FI-14, Structure FI-15, Structure FI-16, Structure FI-17, Structure FI-18, Structure FI-19, Structure FI-20, Structure FI-21, Structure FI-22, Structure FI-23, Structure FI-24, Structure FI-25, Structure FI-26, Structure FI-27, Structure FI-28, Structure FI-29, Structure FI-30, Structure FI-31, Structure FI-32, Structure FI-33, Structure FS-1, Structure FS-2, Structure FS-3, Structure FS-4, Structure FS-5, Structure FS-6, Structure FS-7, Structure FS-8, Structure FS-9, Structure FS-10, Structure FS-11, Structure FS-12, Structure FS-13, Structure FS-14, Structure FS-15, Structure FS-16, Structure FS-17, Structure FS-18, Structure FS-19, Structure FS-20, Structure FT-1, Structure FT-2, Structure FT-3, Structure FT-4, Structure FT-5, Structure FT-6, Structure FT-7, Structure FT-8, Structure FT-9, Structure FT-10, Structure FT-11, Structure FT-12, Structure FT-13, Structure FT-14, Structure FT-15, and Structure FT-16: 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
 Y is selected from the group consisting of H, OH, NHCHO, NHC(═O)R 6 , OC(═O)CH 3 , OC(═O)R 6 , OCH 3 , OC 2 H 5 , OR 6 , CH 3 SO 3 , R 6 SO 3 , NO 2 , CN, CF 3 , OCF 3 , OC 2 F 5 , OC 3 F 7 , F, Br, I, Cl, and substituted and unsubstituted alkyloxyl; 
 
     
       
         
         
             
             
         
       
       is selected from the group consisting of Structure NS-1, Structure NS-2, Structure NS-3, Structure NS-4 and Structure NS-5: 
     
     
       
         
         
             
             
         
       
       X 1  is selected from the group consisting of H, OH, OCH 3 , OC 2 H 5 , OR 6 , C(═O)NH 2 , CH 2 C(═O)NH 2 , CH 2 C(═O)CH 3 , CH 2 C(═O)R 6 , OC(═O)CH 3 , OC(═O)R 6 , CH 2 OCH 3 , CH 3 , C 2 H 5 , R 6 , Cl, F, Br, I, HC═CHCH 3 , HC═CH 2 , CH 2 OCH 3 , CH 2 OR 6 , S(CH 2 ) n —NHR 7 , Structure X 1 -1, Structure X 1 -2, Structure X 1 -3, Structure X 1 -4, Structure X 1 -5, Structure X 1 -6, Structure X 1 -7, Structure X 1 -8, Structure X 1 -9, Structure X 1 -10, Structure X 1 -11, Structure X 1 -12, Structure X 1 -13, Structure X 1 -14, Structure X 1 -15, Structure X 1 -16, Structure X 1 -17, Structure X 1 -18, Structure X 1 -19, Structure X 1 -20, Structure X 1 -21, Structure X 1 -22, Structure X 1 -23, Structure X 1 -24, Structure X 1 -25, Structure X 1 -26, Structure X 1 -27, Structure X 1 -28, Structure X 1 -29, Structure X 1 -30, Structure X 1 -31, Structure X 1 -32, Structure X 1 -33, Structure X 1 -34, Structure X 1 -35, Structure X 1 -36, Structure X 1 -37, Structure X 1 -38, Structure X 1 -39, Structure X 1 -40, Structure X 1 -41, Structure X 1 -42, Structure X 1 -43, Structure X 1 -44, Structure X 1 -45, Structure X 1 -46, Structure X 1 -47, Structure X 1 -48, Structure X 1 -49, Structure X 1 -50, Structure X 1 -51, Structure X 1 -52, Structure X 1 -53, Structure X 1 -54, Structure X 1 -55, Structure X 1 -56, Structure X 1 -57, Structure X 1 -58, Structure X 1 -59, Structure X 1 -60, Structure X 1 -61, Structure X 1 -62, Structure X 1 -63, Structure X 1 -64, Structure X 1 -65, Structure X 1 -66, Structure X 1 -67, Structure X 1 -68, Structure X 1 -69, Structure X 1 -70, Structure X 1 -71, Structure X 1 -72, Structure X 1 -73, Structure X 17 -4, Structure X 1 -75, Structure X 1 -76, Structure X 1 -77, Structure X 1 -78, Structure X 1 -79, Structure X 1 -80, Structure X 1 -81, and Structure X 1 -82: 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       R 5 — taken together with Y is R 6 OCH 2 C(R 5 )═, or by itself is selected from the group consisting of R 6 OOCCH(NHR 7 )(CH 2 ) n C(═O)NH—, R 6 OOCCH(NHR 7 )(CH 2 ) n SC(═O)NH—, CF 3 SCH 2 C(═O)NH—, CF 3 CH 2 C(═O)NH—, CHF 2 SCH 2 C(═O)NH—, CH 2 FSCH 2 C(═O)NH—, NH 2 C(═O)CHFS—CH 2 C(═O)NH—, R 7 NHCH(C(═O)OW)CH 2 SCH 2 C(═O)NH—, R 7 NHCH(L 1 -L 4 -L 2 -W)CH 2 SCH 2 C(═O)NH—, CNCH 2 SCH 2 C(═O)NH—, CH 3 (CH 2 ) n C(═O)NH—, R 7 N═CHNR 7 CH 2 CH 2 S—, R 7 N═C(NHR 7 )NHC(═O)—, R 7 N═C(NHR 7 )NHC(═O)CH 2 , CH 3 C(CI)═CHCH 2 SCH 2 C(═O)NH—, (CH 3 ) 2 C(OR 6 )—, CNCH 2 C(═O)NH—, CNCH 2 CH 2 S—, R 7 HN═CH(NR 7 )CH 2 CH 2 S—, CH 2 ═CHCH 2 SCH 2 C(═O)NH—, CH 3 CH(OH)—, CH 3 CH(OR 8 )—, CH 3 CH(Y 1 )—, (CH 3 ) 2 CH—, CH 3 CH 2 —, CH 3 (CH 2 ) n CH═CH(CH 2 ) m C(═O)NH— wherein, n or m=0, 1, 2, 3, 4, 5, 6, . . . , Structure Rs-1, Structure Rs-2, Structure Rs-3, Structure Rs-4, Structure Rs-5, Structure Rs-6, Structure Rs-7, Structure Rs-8, Structure Rs-9, Structure Rs-10, Structure Rs-11, Structure Rs-12, Structure Rs-13, Structure Rs-14, Structure Rs-15, Structure Rs-16, Structure Rs-17, Structure Rs-18, Structure Rs-19, Structure Rs-20, Structure Rs-21, Structure Rs-22, Structure Rs-23, Structure Rs-24, Structure Rs-25, Structure Rs-26, Structure Rs-27, Structure Rs-28, Structure Rs-29, Structure Rs-30, Structure Rs-31, Structure Rs-32, Structure Rs-33, Structure Rs-34, Structure Rs-35, Structure Rs-36, Structure Rs-37, Structure Rs-38, Structure Rs-39, Structure Rs-40, Structure Rs-41, Structure Rs-42, Structure Rs-43, Structure Rs-44, Structure Rs-45, and Structure Rs-46: 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       W is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure Wa, Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18: 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       Z is selected from the group consisting of CH 2 , S, SO, SO 2 , NH, NR 6 , CHCH 3 , CHCH 2 CH 3 , CR 6 , R 6 , —C(═O)—, and 0; 
       AA represents any amino acids; 
       each m and n is independently selected from the group of 0 and integer; 
       HA is selected from the group consisting of 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; 
       R is selected from the group consisting of nothing, H, CH 2 C(═O)OR 6 , substituted and unsubstituted alkyl, 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 independently selected from the group consisting of H, substituted and unsubstituted alkyl, 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 the group consisting of 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 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 the group consisting of 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 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 the group consisting of 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 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 38  are independently selected from the group consisting of 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 2 I, CH 2 CHF 2 , CH 2 CF 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 2 I, 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 C(═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 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 16  are independently selected from the group consisting of nothing, H, CH 2 C(═O)OR 11 , substituted and unsubstituted alkyl, 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; 
       X is selected from the group consisting of nothing, C(═O), OC(═O), CH 2 , CH, S, NH, NR 6 , and O; 
       X 2  is selected from the group consisting of 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 C(═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 the group consisting of 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 the group consisting of nothing, N, CH, and CY 1 ; 
       X 5  and X 35  are independently selected from the group consisting of nothing, C(═O), OC(═O), CH 2 , CH, S, O and NR 5 ; 
       X 6 , X 36  and X 46  are independently selected from the group consisting of nothing, C(═O), OC(═O), CH 2 , CH, S, O and NR 5 ; 
       X 7  is selected from the group consisting of 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 the group consisting of 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 C(═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 the group consisting of nothing, O, S, —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 the group consisting of nothing, O, S, —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 the group consisting of 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 the group consisting of 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, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NL 3 , or any other pharmaceutically acceptable groups; 
       L 6  is independently selected from the group consisting of 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, CHL 6 , CL 6 L 7 , aryl, heteroaryl, or cyclic groups; and 
       L 7  is independently selected from the group consisting of 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, CHL 6 , CL 6 L 7 , aryl, heteroaryl, or cyclic groups; and 
       any CH 2  groups may be replaced with O, S, or NH. 
     
   
   
       10 . The high penetration composition according to  claim 9  having a structure selected from the group consisting of Structure P-1, Structure P-2, Structure P-3, Structure P-4, Structure P-5, Structure P-6, Structure P-7, 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, Structure I-3, Structure I-4, Structure I-5, Structure I-6, Structure I-7, Structure I-8, Structure I-9, Structure I-10, Structure I-11, Structure I-12, Structure I-13, Structure I-14, Structure I-15, Structure I-16, Structure I-17, Structure I-18, Structure I-19, Structure I-20, Structure I-21, Structure 1-22, Structure I-23, Structure I-24, Structure I-25, Structure I-26, Structure I-27, Structure I-28, Structure I-29, Structure I-30, Structure I-31, Structure I-32, Structure I-33, Structure S-1, Structure S-2, Structure S-3, Structure S-4, Structure S-5, Structure S-6, Structure S-7, Structure S-8, Structure S-9, Structure S-10, Structure S-11, Structure S-12, Structure S-13, Structure S-14, Structure S-15, Structure S-16, Structure S-17, Structure S-18, Structure S-19, Structure S-20, Structure T-1, Structure T-2, Structure T-3, Structure T-4, Structure T-5, Structure T-6, Structure T-7, Structure T-8, Structure T-9, Structure T-10, Structure T-11, Structure T-12, Structure T-13, Structure T-14, Structure T-15, and Structure T-16: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof. 
     
   
   
       11 . A pharmaceutical composition comprising a high penetration composition according to  claim 9  and a pharmaceutically acceptable carrier. 
   
   
       12 . The pharmaceutical composition according to  claim 11 , wherein the pharmaceutically acceptable carrier is polar. 
   
   
       13 . The pharmaceutical composition according to  claim 11 , wherein the pharmaceutically acceptable carrier is selected from the group of alcohol, acetone, ester, water, and aqueous solution. 
   
   
       14 . A method for penetrating a biological barrier, comprising administrating to the biological barrier a pharmaceutical composition according to  claim 11 . 
   
   
       15 . A method for screening a HPP of a antimicrobial or a antimicrobial-related compound for a desired character, comprising the following steps:
 1) covalently linking a functional unit comprising a antimicrobial or a antimicrobial-related compound to a transportational unit through a linker to form a test composition;   2) administrating the test composition to a biological subject or a biological barrier; and   3) determining whether the test composition has a desired character.   
   
   
       16 . The method according to  claim 15 , wherein the desired character is selected from the group consisting of:
 1) the ability of the test composition to penetrate the biological barriers;   2) the ability of the test composition to convert to a parent drug or to an active agent;   3) the penetration rate of the test composition;   4) the efficiency of the test composition; and   5) the efficacy of the test composition.   
   
   
       17 . A method for diagnosing a condition in a biological subject, comprising the following steps:
 1) administrating a composition according to any one of  claim 9  to the biological subject;   2) detecting the presence, location or amount of the composition in the biological subject; and   3) detecting a condition in the biological subject.   
   
   
       18 . The method according to  claim 17 , wherein the composition is labeled. 
   
   
       19 . A method for diagnosing a condition in a biological subject, comprising the following steps:
 1) administrating a composition according to any one of  claim 11  to the biological subject;   2) detecting the presence, location or amount of the composition in the biological subject; and   3) detecting a condition in the biological subject.   
   
   
       20 . The method according to  claim 19 , wherein the composition is labeled. 
   
   
       21 . A method for treating a condition in a biological subject, comprising administrating to the biological subject the high penetration composition according to  claim 9 . 
   
   
       22 . The method according to  claim 21 , wherein the condition is selected from the group consisting of pain, injuries and microorganism related conditions. 
   
   
       23 . The method according to  claim 22 , wherein the microorganism related condition is selected from the group consisting of bacteria-related conditions, protozoa-related conditions, fungi-related conditions and conditions caused by virus. 
   
   
       24 . The method according to  claim 23 , wherein the bacteria-related condition is selected from the group consisting of infections, plague, bubonic plague and pneumonic plague, anthrax, cutaneous anthrax, pulmonary anthrax and gastrointestinal anthrax, 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 
   
   
       25 . The method according to  claim 24 , wherein the infection condition is selected from the group consisting of infection condition in an organ selected from the group consisting of 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. 
   
   
       26 . The method according to  claim 23 , wherein the protozoa-related condition is selected from the group consisting of malaria, sleeping sickness, and toxoplasmosis. 
   
   
       27 . The method according to  claim 23 , wherein the fungi-related condition is selected from the group consisting of aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis. 
   
   
       28 . The method according to  claim 23 , wherein the virus-related condition is selected from the group consisting of influenza, yellow fever and AIDS.