CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Applications 62/052,545, filed on Sep. 19, 2014, and 62/068,984, filed on Oct. 27, 2014, the contents of which are hereby incorporated in their entirety.

BACKGROUND

The diagnosis and therapy of bacterial infections remains a central challenge in medicine. Infections are currently diagnosed by using blood cultures or tissue biopsy; however, these methods can only detect late stage infections that are challenging to treat, and also cannot detect bacterial drug resistance. A major limitation preventing the effective treatment of bacterial infection is an inability to image infections in vivo with accuracy and sensitivity. Consequently, bacterial infections can be diagnosed only after they have become systematic or have caused significant anatomical tissue damage, a stage at which they are challenging to treat owing to the high bacterial burden. Although contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vivo and cannot distinguish infections from other pathologies such as cancer and inflammation. There is a need for the development of contrast agents that can image small numbers of bacteria accurately in vivo.

Bacteria can utilize glycogen, starch, and amylose as carbon sources. Prior to transport through the cell membrane, these polysaccharides are hydrolyzed by the extracellular Î±-amylase into smaller maltodextrins, maltose and isomaltose. The maltose ABC importer (type I) of Escherichia coli enables the bacteria to feed on maltose and maltodextrins (Bordignon et al., Mol Microbiol., 2010, 77(6):1354-1366). Although, maltohexaose contrast agents have been developed to image bacteria, they are hydrolyzed by the serum amylase. There is a great need for the development of more stable targeting agents that can diagnose and treat the bacterial infections.

Murthy et al. report oligosaccharides conjugates for targeting bacteria. See WO/2012/097223.

Hindsgaul reports the preparation of thio galactosides as toxin inhibitor bactericides, virucides, and fungicides. U.S. Pat. No. 5,932,554

Zeng et al. report a process for selective removal of saccharide thioacetyl protective group. CN Patent 103554195.

Gottschaldt et al. report the synthesis of sugar-substituted polypyridine metal complexes and their use as diagnostic, visualization, or therapeutic agents in the treatment of disease. DE Patent 102007032799.

References cited herein are not an admission of prior art.

SUMMARY

This disclosure relates saccharide analogs such as thiomaltose-based analogs for targeting bacteria and related uses. In certain embodiments, the disclosure relates to methods of transferring a molecule of interest into bacteria comprising mixing bacteria with a non-naturally occurring conjugate, wherein the conjugate comprises a thiomaltose-based analog and a molecule of interest under conditions such that the conjugate is transported across the bacterial cell wall. In certain embodiments, the molecule of interest can be a tracer or an antibiotic.

In certain embodiments, the disclosure relates to a composition comprising a tracer molecule conjugated to thiol bridging saccharides. In certain embodiments the tracer molecule is a positron-emitting radionuclide. In certain embodiments, the positron-emitting radionuclide is selected from carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82, and strontium-82. In certain embodiments the tracer is a fluorescent molecule. In certain embodiments, the fluorescent molecule is a fluorescent dye. In certain embodiments, the thiol bridging saccharide is thiomaltose-perylene.

With regard to any of the conjugates disclosed herein, the saccharides can be a polysaccharide of greater than 2, 3, 4, 5, or 6 sugar oligomers bridged by one or more thiol linkages which are typically isolated or substantially purified. In some embodiments, the polysaccharide comprises glucose oligomers, e.g., maltohexaose, a polysaccharide with 6 glucose oligomers. Typically, the glucose oligomers are linked by a thiol bridging alpha 1â†’4, i.e., 1 to 4, covalent bond. In certain embodiments, the disclosure contemplates thiomaltose-based analog of glucose oligomers and/or 2-deoxyglucose oligomers wherein one or more of the glucose monomers are substituted with a positron-emitting radionuclide ¹⁸F.

In certain embodiments, any of the compounds or saccharide analogs disclosed herein or derivatives can be optionally substituted with one or more, the same or different, substituents.

In certain embodiments, the disclosure relates to an antibiotic conjugated to a saccharide analog disclosed herein. In certain embodiments, the antibiotic is selected from the group comprising sulfonamides, carbapenems, penicillins, diaminopyrimidines, quinolones, beta-lactam antibiotics, cephalosporins, tetracyclines, notribenzenes, aminoglycosides, macrolide antibiotics, polypeptide antibiotics, nitrofurans, nitroimidazoles, nicotinin acids, polyene antibiotics, imidazoles, glycopeptides, cyclic lipopeptides, glycylcyclines, and oxazolidinones. In certain embodiments, the antibiotic is selected from dapsone, paraaminosalicyclic, sulfanilamide, sulfamethizole, sulfamethoxazole, sulfapyridine, trimethoprim, pyrimethamine, nalidixic acid, norfloxacin, ciproflaxin, cinoxacin, enoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, pefloxacin, sparfloxacin, trovafloxacin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, hetacillin, oxacillin, mezlocillin, penicillin G, penicillin V, piperacillin, cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefaloniumn, cefaloridin, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, ceftezole, cefaclor, cefonicid, ceforanide, cefprozil, cefuroxime, cefuzonam, cefmetazole, cefoteta, cefoxitin, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxirme, cefodizime, cetbperazone, cefotaxime, cefotiam, cefpimizole, cefpiramide, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolen, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefepime, moxolactam, imipenem, ertapenem, meropenem, aztreonam, oxytetracycline, chlortetracycline, clomocycline, demeclocycline, tetracycline, doxycycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, chloramphenicol, amikacin, gentamicin, farmycetin, kanamycin neomicin, neomycin, netilmicin, streptomycin, tobramycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, telithromycin, polymyxin-B, colistin, bacitracin, tyrothricin, notrifurantoin, furazolidone, metronidazole, tinidazole, isoniazid, pyrazinamide, ethionamide, nystatin, amphotericin-B, hamycin, miconazole, clotrimazole, ketoconazole, fluconazole, rifampacin, lincomycin, clindamycin, spectinomycin, chloramphenicol, clindamycin, colistin, fosfomycin, loracarbef, nitrofurantoin, procain, spectinomycin, tinidazole, ramoplanin, teicoplanin, and vancomycin.

In certain embodiments, the disclosure relates to a method of transferring a molecule of interest into bacteria comprising mixing bacteria with a non-naturally occurring conjugate under conditions such that the conjugate is transported across the bacterial cell wall wherein the conjugate comprises a saccharide analog and a molecule of interest.

In certain embodiments, the disclosure relates to an imaging method comprising a) administering a tracer molecule conjugated to a saccharide analog to a subject; and b) scanning the subject for a physical property of the tracer molecule. In certain embodiments the imaging method further comprises the step of detecting the physical property of the tracer molecule and creating an image highlighting the location of the tracer molecule in the subject.

In certain embodiments, the disclosure relates to a method of treating or preventing a bacterial infection comprising administering an effective amount of an isolated conjugate to a subject in need thereof wherein the isolated conjugate comprises an antibiotic and a saccharide analog. In certain embodiments the isolated conjugate is administered in combination with another antibiotic.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates saccharide analogs, e.g., thiomaltose-based analogs designed to image bacterial infections. Left side: illustrates bacteria internalized PET contrast agent (1) with an ¹⁸F derivatized maltodextrin probe (MDP) (1) through the maltodextrin transporter (2). ¹⁸F-thiomaltose is designed to image bacteria in vivo by targeting the maltodextrin transport pathway. ¹⁸F-thiomaltose is internalized by bacteria. Maltodextrin transporters are not present in mammalian cells and ¹⁸F-thiomaltose-based analogs therefore have high specificity for bacteria over mammalian cells. Right side: illustrates imaging bacterial infections in implanted device due to robust accumulation of ¹⁸F-MDPs. Systemic injection (4) of ¹⁸F-MDPs can be used to image bacterial implant infections and generate an imaging agent that can diagnose early stage bacterial implant infections at the site of implant (3).

FIG. 2 Synthesis of thiomaltose-perylene: a) NaOCH₃, MeOH, 55%. b) Tf₂O, DCM-Pyridine, 63%. c) TEA, DMF, 38%. d) NaOCH₃, MeOH, 83%. e) Pyridine, Ac₂O, 78%. f) NH₂NH₂.HOAc, DMF, 81%. g) Trichloroacetonitrile, DBU, DCM, 97%. h) Azidopropanol, TMSOTf, DCM, 63%. i) 1. alkyne-perylene, CuI, DIPEA, DMF; 2. LiOH, MeOH, H2O, 65% in two steps

FIG. 3 Synthesis of ¹⁸F-thiomaltose: a) 2, CuI, DIPEA, DMF. b) 1. K¹⁸F, CH₃CN, 110Â° C.; 2. NaOH, H₂O.

FIG. 4 schematically illustrates the retrosynthesis of thiomaltose.

FIG. 5 schematically illustrates the synthesis of the glucose building block.

FIG. 6 schematically illustrates the synthesis of the galactose building block.

FIG. 7 schematically illustrates the synthesis of the galactose building block.

FIG. 8 schematically illustrates the synthesis of the galactose building block.

FIG. 9 schematically illustrates glycosylation.

FIG. 10 schematically illustrates the synthesis of perylene-thiomaltose.

FIG. 11 shows uptake of thiomaltose-perylene in Mtb cells. Thiomaltose-perylene (50 Î¼M), and uptake was measured using a plate reader (fluorescence intensity at 410/480).

FIG. 12 shows a table of uptake of thiomaltose-perylene in Salmonella and pseudomonas cells.

FIG. 13 shows uptake studies in bacterial and mammalian cells. Bacteria (E. coli) and macrophages were incubated with thiomaltose-perylene (20 Î¼M) for 2 hours. Cells were washed 3 times with PBS. Cells were lysed using they lysis buffer. The fluorescence intensity from bacteria and mammalian cells was measured by plate reader at 410/480 and the background of lysis buffer was subtracted. The protein content was analyzed by BCA assay. The uptake of thiomaltose-perylene in bacteria was 98 fold higher than in macrophages.

FIG. 14 shows data indicating that thiomaltose is resistant to maltase hydrolysis. Maltose is hydrolyzed completely in 3 hours, whereas thiomaltose is less than 1% hydrolyzed.

FIG. 15 illustrates certain embodiments of the disclosure.

FIG. 16 illustrates certain embodiments of the disclosure.

FIG. 17 illustrates certain embodiments of the disclosure.

FIG. 18 illustrates certain embodiments of the disclosure.

FIG. 19 shows data indicating that the thiomaltose-radezolid inhibits bacterial growth. E. Coli were grown in a 96 well plate, starting at an O.D. of 0.05. Thiomaltose-radezolid was added to the bacteria, and the bacteria were shaken at 37 C between 1-24 hours. The O.D. of the bacteria was then measured and normalized to untreated bacteria IC₅₀at 24 hours is approximately 0.5 micromolar.

FIG. 20 illustrates certain embodiments of the disclosure.

FIG. 21 illustrates certain embodiments of the disclosure.

FIG. 22 illustrates certain embodiments of the disclosure.

FIG. 23 shows data indicating TM-R can effectively kill P. aeruginosa. TM-R and free radezolid were incubated with P. aeruginosa for 24 hours. OD600 were used to determine the bacteria growth.

FIG. 24 illustrates certain embodiments of the disclosure.

FIG. 25 illustrates certain embodiments of the disclosure.

DETAILED DESCRIPTION

Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that can need to be independently confirmed.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which can be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

Targeting Bacteria

A central problem in imaging bacterial infections is to develop targeting strategies that can deliver large quantities of imaging probes to bacteria. This has been challenging because typical imaging probes target the bacterial cell wall and cannot access the bacterial intracellular volume. Although numerous contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vivo, and cannot distinguish infections from other pathologies such as cancer and inflammation. Within certain embodiments, the disclosure relates to a thiomaltose-based imaging probe which can detect bacteria in vivo with a sensitivity two orders of magnitude higher than previously reported, and can detect bacteria using a bacteria-specific mechanism that is independent of host response and secondary pathologies.

In certain embodiments, the thiomaltose-based imaging probe is composed of a fluorescent dye conjugated to a thiomaltose-based analog and is rapidly internalized through the bacteria-specific maltodextrin transport pathway, endowing the thiomaltose-based imaging probes with a unique combination of high sensitivity and specificity for bacteria. Certain thiomaltose-based imaging probes selectively accumulate within bacteria at millimolar concentrations, and are a thousand-fold more specific for bacteria than mammalian cells. Furthermore, thiomaltose-based imaging probes can image as few as 10⁵colony-forming units in vivo and can discriminate between active bacteria and inflammation induced by either lipopolysaccharides or metabolically inactive bacteria.

Contrast agents that are robustly internalized through the bacteria-specific maltodextrin transporter and can image bacterial infections in vivo with improved sensitivity and specificity (see FIGS. 11-14). Thiomaltose-based imaging probes can deliver millimolar concentrations of imaging probes into bacteria, making it possible to image low numbers of bacteria. Thiomaltose-based imaging probes also have high specificity for bacteria because mammalian cells do not express the maltodextrin transporter and cannot internalize contrast agents conjugated to thiomaltose-based analogs (FIG. 13). Thiomaltose-based imaging probes are typically composed of Î± (1â†’4)-thiol linked glucose oligomers. Because thiomaltose-based imaging probes are typically hydrophilic and membrane impermeable, they are efficiently cleared from uninfected tissues in vivo, leading to a low background. Furthermore, the lumen of intestinal tissues or the outer layers of the skin are not permeable to glucose oligomers. Thiomaltose-based imaging probes delivered systemically should therefore not be internalized by the resident bacterial microflora present in healthy subjects.

Conjugates, Derivatives, and Related Compounds

In certain embodiments, the disclosure relates to compounds of formula I,

Q-E-Gâ€ƒâ€ƒFormula I

or salts thereof wherein,

Q is a polysaccharide comprising a 1 to 4-thiol or oxygen linkage such as thiomaltose;

E is a linking group; and

G is a tracer, a drug, an antibiotic, an azide group, or other molecule of interest.

In certain embodiments, Q is a thiomaltose-based analog comprising glucose, a glucose

derivative, and/or a substituted glucose oligomer.

In certain embodiments, E contains a triazole positioned between linking groups such as the

following groups alone or in combination, methylene, ethylene, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, heteroaromatic, or saturated or unsaturated hydrocarbon groups.

In certain embodiments, E can be represented by a formula:

[Image Omitted]

wherein the symbol [Image Omitted] represents the point of attachment to Q and G;

mâ€² is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

Râ€²¹, Râ€³¹, Râ€²²and Râ€³²are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;

X¹, X²and Y is each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH2CH2O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000;

r can be 1 to 22.

In certain embodiments, E can be connected to Q via the the anomeric carbon at the reducing end of the polysaccharide

In certain embodiments, the disclosure relates to compounds of formula I with Formula IA

[Image Omitted]

or salts thereof wherein,

A is independently O or S at each occurrence;

n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

E is a linking group, for instance as defined above;

G is a molecule of interest such as a radionuclide, fluorescent moiety, an antibiotic, or an azide group;

R1, R2, R3, and R4, are each individually and independently a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;

R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and

R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, A must be S at least once or all of A are S.

In certain embodiments, n is 5 or 6 or more, or n is 3 or 4 or more.

In certain embodiments, R2, R3, and R4 are hydrogen or alkanoyl optionally substituted with R5.

In certain embodiments, R1 is hydrogen, halogen, or hydroxy substituted with a protecting group.

In certain embodiments, R1 is ¹⁸F.

In certain embodiments, E is triazole positioned between linking groups such as the following groups alone or in combination, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, heteroaromatic, or hydrocarbon groups.

In certain embodiments, G is ¹⁸F.

Certain embodiments include compounds of Formula IA-1:

[Image Omitted]

Wherein A is either S or O, and Aâ€² is O, provided that at least one A is S.

In certain embodiments, nâ€² 1 or 2, nâ€² is 5 or 6 or more, or nâ€² is 3 or 4 or more.

In certain embodiments, R², R³, and R⁴are hydrogen or alkanoyl optionally substituted with R5.

In certain embodiments, R¹is hydrogen, halogen, or hydroxyl, optionally substituted with a protecting group.

In certain embodiments, R¹is ¹⁸F.

E is a linker, and in certain embodiments, E can be represented by a formula:

[Image Omitted]

wherein the symbol [Image Omitted] represents the point of attachment to Aâ€² and G;

mâ€² is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

Râ€²¹, Râ€³¹, Râ€²²and Râ€³²are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;

X¹, X²and Y is each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH2CH2O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000;

r can be 1 to 22.

In certain embodiments, E is triazole positioned between linking groups such as the following groups alone or in combination, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, heteroaromatic, or hydrocarbon groups.

In certain embodiments, G is ¹⁸F.

Certain embodiments include thioglycoside compounds of Formula IA-2:

[Image Omitted]

Wherein R¹-R⁴, nâ€², E and G are as defined above. In certain embodiments, R², R³and R⁴are each hydrogen, and R¹is either hydroxyl, hydrogen or halogen, preferably ¹⁸F.

In certain embodiments, the disclosure relates to compounds of formula I with formula IB

[Image Omitted]

or salts thereof wherein,

A is O or S at each occurrence provided A must be S at least once or all of A are S;

n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

Râ€² and Râ€³ are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;

X and Y are at each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH2CH2O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000;

r can be 1 to 22;

G is a radionuclide, fluorescent molecule, an antibiotic, or an azide group;

R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;

R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and

R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, thylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,

methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, X or Y is a di-substituted 1,2,3-triazole.

In certain embodiments, the compound of Formula IB can be represented by the compound of Formula IB-1:

[Image Omitted]

or salts thereof wherein,

A is O or S at each occurrence provided A must be S at least once or all of A are S;

Aâ€² is O;

nâ€² is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14;

mâ€² is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

Râ€²¹, Râ€³¹, Râ€²²and Râ€³²are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;

X¹is in each occurrence absent;

X²and Y are at each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH2CH2O)â€”, â€”(CH₂)â€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000;

r can be 1 to 22;

G is a radionuclide, fluorescent molecule, an antibiotic, or an azide group;

R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;

R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and

R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, thylamino, dimethylamino, diethylamino, N-methyl-N-ethyl amino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,

methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, X²is a di-substituted 1,2,3-triazole, in other embodiments, Y is absent, and in certain preferred embodiments, X²is a di-substituted 1,2,3-triazole and Y is absent.

In some embodiments, G can be the following:

[Image Omitted]

wherein the symbol [Image Omitted] represents the point of attachment to E;

U is N or CR¹¹;

W is N or CR⁹;

Z is a carbocyclic or heterocyclic ring;

R⁷is alkyl, carbocyclyl, or aryl, wherein R⁷is optionally substituted with one or more R¹³; or R⁷and R¹¹form a heterocarbocyclic ring optionally substituted with R¹³;

R⁸is hydrogen, alkyl or alkanoyl;

R⁹is a hydrogen or halogen;

R¹⁰is hydrogen, alkoxy, amino, or alkyl;

R¹¹is hydrogen, alkoxy, or halogen; and

R¹²is hydrogen;

R¹³is in each occurrence independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethyl amino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. In certain preferred embodiments, R7 is cyclopropyl or phenyl, optionally substituted by one or more fluorine atoms.

In certain embodiments, Z can have the formula:

[Image Omitted]

wherein the symbol [Image Omitted] represents the point of attachment to E or or the quinolone fragment and R¹³is as defined above. In preferred embodiments, R¹³is in each case independently selected from hydrogen, methyl, or ethyl.

In some embodiments, G can be the following:

[Image Omitted]

wherein the symbol [Image Omitted] represents the point of attachment to E;

R⁷is hydrogen, alkyl, carbocyclyl, or aryl, wherein R⁷is optionally substituted with one or

more, the same or different R¹³;

R⁸, R⁹, R¹⁰, and R¹¹are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R⁸, R⁹, R¹⁰, and R¹¹are optionally substituted with one or more, the same or different, R¹³;

R¹²is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R¹³;

R¹³is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

It certain preferred embodiments, R¹²is acetylamino.

In certain embodiments, G can be:

[Image Omitted]

wherein the symbol [Image Omitted] represents the point of attachment to E.

For embodiments in which G is â€”(CH₂)_x¹⁸F, it is preferred that p is 0.

In certain embodiments, the disclosure relates to compounds of formula I with formula IC,

[Image Omitted]

or salts thereof wherein,

n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

A is O or S at each occurrence provided A must be S at least once or all of A are S;

E is a linking group;

Q is N in the ring of Z, or N is an amino or alkylamino group attached to the Z ring; or Q is O of an oxygen attached to the Z ring, wherein the Z ring can be optionally substituted with one or more, the same or different, R13;

U is N or CR11;

W is N or CR9;

Z is a carbocyclic or heterocyclic ring;

R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;

R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;

R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

R7 is alkyl, carbocyclyl, or aryl, wherein R7 is optionally substituted with one or more, the same or different R13; or R7 and R11 form a heterocarbocyclic ring optionally substituted

with R13;

R8 is hydrogen, alkyl or alkanoyl;

R9 is a hydrogen or halogen;

R10 is hydrogen, alkoxy, amino, or alkyl;

R11 is hydrogen, alkoxy, or halogen; and

R12 is hydrogen;

R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, E is â€”(CRâ€²Râ€³X)_mâ€”(CRâ€²Râ€³Y)_pâ€” wherein

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

Râ€² and Râ€³ are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;

X and Y are at each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH₂CH₂O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000; and

r can be 1 to 22.

In certain embodiments, the disclosure relates to compounds of formula I with formula ID,

[Image Omitted]

or salts thereof wherein,

U is N or CR11;

W is N or CR9;

A is O or S at each occurrence provided A must be S at least once or all of A are S;

n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

Râ€² and Râ€³ are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;

X and Y are at each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH₂CH₂O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000;

r can be 1 to 22;

R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;

R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;

R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

R7 is alkyl, carbocyclyl, or aryl, wherein R7 is optionally substituted with one or more, the same or different R13; or R7 and R11 form a heterocarbocyclic ring optionally substituted with R13;

R8 is hydrogen, alkyl or alkanoyl;

R9 is a hydrogen or halogen;

R10 is hydrogen, alkoxy, amino, or alkyl;

R11 is hydrogen, alkoxy, or halogen; and

R12 is hydrogen;

R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to compounds of formula I with formula IF,

[Image Omitted]

or salts thereof wherein,

n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

A is O or S at each occurrence provided A must be S at least once or all of A are S;

E is a linking group; for example, of formula

In certain embodiments, E can be represented by a formula:

[Image Omitted]

wherein the symbol [Image Omitted] represents the point of attachment to A and the triazole

mâ€² is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1718, 19, 20, 21, 22, or 23;

Râ€²¹, Râ€³¹, Râ€²²and Râ€³²are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;

X¹is each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• )Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH2CH2O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

X²and Y are at each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH2CH2O)_q, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000;

r can be 1 to 22;

R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;

R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;

R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethylamino, dimethylamino, diethylamino N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

R7 is hydrogen, alkyl, carbocyclyl, or aryl, wherein R7 is optionally substituted with one or

more, the same or different R13;

R8, R9, R10, and R11 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, R10, and R11 are optionally substituted with one or more, the same or different, R13;

R12 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13;

R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, E is â€”(CRâ€²Râ€³X)_mâ€”(CRâ€²Râ€³Y)_pâ€” wherein

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

In certain embodiments, E is â€”(CH2)_mâ€” wherein m is is 1, 2, or 3.

Râ€² and Râ€³ are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;

X and Y are at each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”Nâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH₂CH₂O)_qâ€”, â€”(CH₂)â€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000; and

r can be 1 to 22.

In certain embodiments, the disclosure relates to compounds of formula I with formula IG,

[Image Omitted]

or salts thereof wherein,

n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

A is O or S at each occurrence provided A must be S at least once or all of A are S;

E is a linking group; for example a formula:

[Image Omitted]

wherein the symbol [Image Omitted] represents the point of attachment to A and triazole;

mâ€² is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

Râ€²¹, Râ€³¹, Râ€²²and Râ€³²are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;

X¹is each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• )Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH2CH2O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

X²and Y are at each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(Câ• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Câ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH2CH2O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000;

r can be 1 to 22;

G is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest;

R1, R2, R3, and R4, are each individually and independently â€”(Câ• O)OCH₂(Câ• O)alkyl, â€”O(Câ• O)OCH₂(Câ• O)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;

R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;

R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

R7 is â€”(Câ• O)OCH₂O(Câ• O)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R13;

R13 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R14;

R14 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, E is â€”(CRâ€²Râ€³X)_mâ€”(CRâ€²Râ€³Y)_nâ€” wherein

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;

In certain embodiments, E is â€”(CH₂)_mâ€” wherein m is is 1, 2, or 3.

Râ€² and Râ€³ are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;

X and Y are at each occurrence individually and independently â€”Oâ€”, â€”Sâ€”, â€”Sâ€”Sâ€”, â€”NHâ€”, â€”(Câ• O)â€”, â€”NH(â• O)â€”, (Câ• O)NHâ€” â€”O(Câ• O)â€”, â€”(Oâ• O)Oâ€”, â€”S(Câ• O)â€”, â€”(Câ• O)Sâ€”, â€”SOâ€”, â€”SO₂, â€”NHSO₂â€”, â€”SO₂NHâ€”, â€”(CH₂CH₂O)_qâ€”, â€”(CH₂)_râ€”, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;

q can be 1 to 1000; and

r can be 1 to 22.

In certain embodiments, the disclosure relates to compounds of formula I with formula IH,

[Image Omitted]

or salts thereof wherein,

n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

A is O or S at each occurrence provided A must be S at least once or all of A are S;

E is a linking group;

R1, R2, R3, and R4, are each individually and independently independently â€”(Câ• O)OCH₂(Câ• O)alkyl, â€”O(Câ• O)OCH₂(Câ• O)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;

R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;

R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R13;