Conjugate-based antifungal and antibacterial prodrugs

Abstract

The invention provides conjugate-based antifungal or antibacterial prodrugs formed by coupling at least one antifungal agent or antibacterial agent with at least one linker and/or carrier. The prodrugs are of formula: (i) (AFA) m -X-(L) n ; (ii) [(AFA) m′ -X] p -L; (iii) AFA-[X-(L) n′ ] q ; or (iv) (AFA) m″ -X, wherein: AFA is an antifungal agent or an antibacterial agent; L is a carrier; X is a linker; m ranges from 1 to 10; n ranges from 2 to 10; m′ is 1 to 10; p is 1 to 10; n′ is 1 to 10; and q is 1 to 10, provided that q′ and n are not both 1; and m″ is 1 to 10. The invention also provides nonaparticles comprising the conjugate-based prodrugs. Additionally, the invention also provides non-conjugated antifungal and antibacterial agents in the form of nanoparticles.

1 . A conjugate-based antifungal or antibacterial prodrug of formula:
 (i) (AFA) m -X-(L) n , wherein: AFA is an antifungal agent or an antibacterial agent; L is a carrier; X is a linker; m ranges from 1 to 10; and n ranges from 2 to 10;   (ii) [(AFA) m′ -X] p -L, wherein: AFA is an antifungal agent or an antibacterial agent; L is a carrier; X is a linker; m′ is 1 to 10; and p is 1 to 10;   (iii) AFA-[X-(L) n′ ] q , wherein: AFA is an antifungal agent or an antibacterial agent; L is a carrier; X is a linker; n′ is 1 to 10; and q is 1 to 10, provided that q′ and n are not both 1; or   (iv) (AFA) m″ -X, wherein: AFA is an antifungal agent or an antibacterial agent; X is a linker; and m″ is 1 to 10.   
     
     
         2 . The conjugate-based prodrug of  claim 1 , wherein:
 (i) m′ and p are 1;   (ii) q is 1 and n′ is 2; or   (iii) m″ is 2.   
     
     
         3 . The conjugate-based prodrug of  claim 1 , wherein the conjugate-based prodrug is formulated as a nanoparticle. 
     
     
         4 . The conjugate-based prodrug of  claim 1 , wherein the prodrug is formulated as a liposome, polymeric nanoparticle, nanoemulsion, self-microemulsifying drug delivery system (SMEDD), solid-lipid nanoparticle, nano-structured liquid crystal, or any combination thereof. 
     
     
         5 . The conjugate-based prodrug of  claim 1 , wherein the linker is a cleavable linker. 
     
     
         6 . The conjugate-based prodrug of  claim 5 , wherein the linker is cleaved by an esterase. 
     
     
         7 . The conjugate-based prodrug of  claim 1 , wherein the linker is selected from group consisting of; 
       
         
           
           
               
               
           
         
       
       wherein R 2a  is a hydroxyl protecting group; R 2b  is C 1 -C 6 alkyl, which can be optionally substituted or interspersed with one or more heteroatoms, aryls, heteroaryls, cyclyls and heterocyclyls; and R N  is absent, H, C 1 -C 6 alkyl, or acyl, each of which can be optionally substituted;
 (ii) a polyethylene glycol of formula —CH 2 CH 2 [OCH 2 CH 2 ] a OHC 2 CH 2 —, wherein a is 1-50; 
 (iii) —CH 2 C(R 3a R 3b )CH(OR 3c )C(O)N(R 3d )—(CH 2 ) b —, wherein R 3a  and R 3b  are independently H or C 1 -C 6 alkyl, which can be optionally substituted and/or interspersed with one or more heteroatoms, aryls, heteroaryls, cyclyls, and heterocyclyls; R 3c  is H or a carrier; R 3d  is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which can be optionally substituted; and b is 1-10; 
 
       
         
           
           
               
               
           
         
       
       wherein R 4  is halo, CN, CF 3 , alkyl, alkenyl, cyclyl, heterocyclyl, aryl, heteroaryl, NO 2 , OR 6 , OC(O)R 4a , OC(O)OR 4a , N(R 4a ) 2 , NHC(O)R 4a , NHC(O)OR 4a , C(O)R 4a , C(O)OR 4a , SR 4a , or SO 2 R 4a , each of which can be optionally substituted; R 48  is independently for each occurrence, H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which can be optionally substituted; and c is 0 to 4;
 (v) —CH 2 CH(R 6 )—, wherein R is H or C 1 -C 6  alkyl, which can be optionally substituted and/or interspersed with one or more heteroatoms, aryls, heteroaryls, cyclyls, and heterocyclyls; 
 (vi) —CH(R 7 )C(O)—, wherein R 7  is H, C 1 -C 6 alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which can be optionally substituted and/or interspersed with one or more heteroatoms, aryls, heteroaryls, cyclyls and heterocyclyls; 
 (vii) —CH(R 8 )OC(O)-L′-C(O)O—, wherein Re is H or C 1 -C 6 alkyl; and L′ is an alkyl group, which can be optionally substituted and/or interspersed with one or more heteroatoms, aryls, heteroaryls, cyclyls or heterocylcyls, each of which can also be optionally substituted; 
 (viii) —CH(R 9 )OC(O)—, —CH(R 9 )OC(O)-L′-, —CH(R 9 )OC(O)-L′-Y— or —CH(R 9 )OC(O)-L′-Y—C(O)—, wherein R 9  is H or C 1 -C 6  alkyl; Y is O, S, or NH; and L′ is an alkyl, which can be optionally substituted and/or interspersed one or more heteroatoms, aryls, heteroaryls, cyclyls or heterocylcyls, each of which can be optionally substituted; 
 (ix) —CH(R 10a )OC(O)-L′-C(O)OCH(R 10b )—, wherein R 10a  and R 10b  are independently H or C 1 -C 6  alkyl, which can be optionally substituted; and L′ is C 1 -C 20  alkyl, which can be optionally substituted and/or interspersed one or more heteroatoms, aryls, heteroaryls, cyclyls or heterocylcyls, each of which can be optionally substituted; 
 (x) —C(O)-L′-C(O)—, —C(O)-L′-, —C(O)-L′-Y—, or —C(O)-L′-Y—C(O)—, wherein Y is O, S, or NH; and L′ is an alkyl, which can be optionally substituted and/or interspersed one or more heteroatoms, aryls, heteroaryls, cyclyls or heterocylcyls, each of which can be optionally substituted; 
 (xi) —C(O)-L′-C(O)O—[CH 2 CH 2 O] v′ —, wherein v′ is 1-500 and L′ is an alkyl, which can be optionally substituted and/or interspersed one or more heteroatoms, aryls, heteroaryls, cyclyls or heterocylcyls, each of which can be optionally substituted; 
 (xii) PLGA; 
 (xiii) a direct bond; 
 (xiv) a dicarboxylic acid; 
 (xv) a beta-hydroxy acid; 
 (xvi) a polyhydroxy acid; and 
 (xvii) any combinations of (i)-(xvi). 
 
     
     
         8 . The conjugate-based prodrug of  claim 1 , wherein the antifungal agent comprises an azole moiety or a hydroxyl group. 
     
     
         9 . The conjugate-based prodrug of  claim 1 , wherein:
 (i) the antifungal agent is selected from the group consisting of Fluconazole, Isavuconazole, Itraconazole, Ketoconazole, Miconazole, Clortrimazole, Voriconazole, Posaconazole, Ravuconazole, natamycin, lucensomycin, nystatin, amphotericin B, echinocandins, Cancidas, pradimicins, beanomicins, nikkomycins, sordarins, allylamines, Triclosan, Piroctone, phenpropimorph, terbinafine, antifungal peptide, and derivatives and analogs thereof; or   (ii) the antibacterial agent is selected from the group consisting of macrolides or ketolides such as erythromycin, azithromycin, clarithromycin and telithromycin; beta-lactams including penicillin, cephalosporin, and carbapenems such as carbapenem, imipenem, and meropenem; monobactams such as penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, meziocillin, piperacillin, azlocillin, temocillin, cepalothin, cephapirin, cephradine, cephaloridine, cefazolin, cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime, and astreonam; quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, ganefloxacin, gemifloxacin and pazufloxacin; antibacterial sulfonamides and antibacterial sulphanilamides, including para-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and sulfathalidine; aminoglycosides such as streptomycin, neomycin, kanamycin, paromycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekalin and isepamicin; tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline; rifamycins such as rifampicin (also called rifampin), rifapentine, rifabutin, bezoxazinorifamycin and rifaximin; lincosamides such as lincomycin and clindamycin; glycopeptides such as vancomycin and teicoplanin; streptogramins such as quinupristin and daflopristin; oxazolidinones such as linezolid; polymyxin, colistin and colymycin; and trimethoprim and bacitracin.   
     
     
         10 . The conjugate-based prodrug  claim 1 , wherein the carrier is a polymer; a fatty acid; a carboxylated polymer, a hydroxylated polymer, a polyethylene glycol; a carboxylated PEG, a fatty acid comprising a C 6 -C 26  alkyl, which can be optionally substituted and/or interspersed with a heteroatom, aryl, heteroaryl, cyclyl, or heterocyclyl; an amino acid; a peptide; a nucleic acid; a glycerol, substituted glycerol, an antibacterial agent, an antifungal agent; a alpha-hydroxy acid, a beta-hydroxy acid, a dicarboxylic acid, oxadiacid, and any combinations thereof. 
     
     
         11 . The conjugate-based prodrug of  claim 1 , wherein:
 (i) the carrier is a fatty acid selected from the group consisting of Caprylic acid, Pelargonic acid, Capric acid, Undecylic acid, Lauric acid, Tridecylic acid, Myristic acid, Pentadecylic acid, Palmitic acid, Heptadecanoic acid, Stearic acid, Nonadecylic acid, Arachidic acid, Heneicosylic acid, Behenic acid, Tricosylic acid, Lignoceric acid, Pentacosylic acid, Cerotic acid, Heptacosylic acid, Montanic acid, Myristoleic acid, Palmitoleic acid, Sapienic acid, Oleic acid, Elaidic acid, Vaccenic acid, Linoleic acid, Linoelaidic acid, α-Linolenic acid, γ-Linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Erucic acid, Docosahexaenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid, undecylenic acid, cis-13-docosenoic acid, neoheptanoic acid, neononanoic acid, neodecanoic acid, isostearic acid, 10-undecaenoic acid, adapalene, undecylenic acid; palmitic acid; oleaic acid, linoleic acid, lauric acid, and any combinations thereof;   (ii) the carrier is polymer selected from the group consisting of PLGA, PLA, PEG, chitosan, pullulan, polylactides, polyglycolides, polycaprolactones, copolymers of polylactic acid and polyglycolic acid, polyanhydrides, polyepsilon caprolactone, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polydihydropyrans, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polymethyl methacrylate, chitin, chitosan, copolymers of polylactic acid and polyglycolic acid, poly(glycerol sebacate) (PGS), and copolymers, terpolymers, gelatin, collagen, silk, chitosan, alginate, cellulose, poly-nucleic acids, cellulose acetates (including cellulose diacetate), polyethylene, polypropylene, polybutylene, polyethylene terphthalate (PET), polyvinyl chloride, polystyrene, polyamides, nylon, polycarbonates, polysulfides, polysulfones, hydrogels (e.g., acrylics), polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose, copolymers of urethane/carbonate, copolymers of styrene/maleic acid, poly(ethylenimine), Pluronic (Poloxamers 407, 188), Hyaluron, heparin, agarose, Pullulan, ethylene/vinyl alcohol copolymers (EVOH), and copolymers including one or more of the foregoing; or   (iii) the carrier is selected from the group consisting of lys-his-lys-his-lys-his hexapeptide; L- or D-tyrosine; L- or D-serine; L- or D-threonine; a peptide of 2-10 amino acids; and pullulan.   
     
     
         12 . The conjugate-based prodrug of  claim 1 , wherein the conjugate is ketoconazole-methylene-PLGA, ketoconazole-pyridoxine-undecylenic acid, ketoconazole-pamthenol dimer, ketoconazole-propylene glycol-hexapeptide, ketoconazole-lactic acid-chitosan, ketoconazole-methylene-oxaacid acid-chitosan, ketoconazole-methylene-oxadiacid dimer, ketoconazole-methylene-glutamic acid dimer, clindamycin lauric acid conjugate, clindamycin-glycolic acid-PLGA conjugate, clindamycin-succinic acid-PLGA conjugate, clindamycin-adapalene conjugate, erythromycin-lauric acid conjugate, erythromycin-lactic-lauric acid conjugate, lauric acid-PLGA-erythromycin conjugate, adapalene-triethyleneglycon-erythromycin conjugate, clindamycin dimer, clindamycin dimer with azelaic acid, clindamycin dimer with carboxylated PEG, clindamycin dimer with glutamic acid, clindamycin dimer with oxydiacetic acid, clindamycin triclosan conjugate, clindamycin-glutamic acid-triclosan conjugate, or clindamycin-oxydiacetic acid-triclosan conjugate. 
     
     
         13 . A nanoparticle comprising: (i) a first component selected from antifungal agents, antibacterial agents, or a combination thereof; and (ii) a second component select from a lipid, a polymer or a combination thereof. 
     
     
         14 . The nanoparticle of  claim 13 , wherein the first component and the second component are not covalently linked to each other. 
     
     
         15 . The nanoparticle of  claim 13 , wherein the nanoparticle comprises further comprises a surfactant. 
     
     
         16 . The nanoparticle of  claim 13 , wherein the nanoparticle further comprises a carrier or excipient. 
     
     
         17 . A personal care composition comprising an effective amount of a conjugate-based prodrug of  claim 1 . 
     
     
         18 . The personal care composition of  claim 17 , wherein the composition further comprises a pharmaceutical or a topical agent. 
     
     
         19 . A method of treating or preventing a fungal or bacterial infection in a subject, the method comprising administering to a composition of  claim 17 . 
     
     
         20 . A personal care composition comprising a nanoparticle of  claim 13 .