Development of Prodrugs Possessing a Nitric Oxide Donor Diazen-1-Ium-1,2-Diolate Noiety Using in Vitro/in Silico Predictions

A method of pairing a therapeutic agent with an appropriate nitric oxide donor to create an effective prodrug molecule, comprising:

• (i) obtaining in vitro or in silico pharmacokinetic and/or pharmacodynamic data of the therapeutic agent, nitric oxide donor and nitric oxide from said donor;
• (ii) placing the data into a physiologically-based pharmacokinetic/pharmacodynamic model comprising:
• (a) a first compartment model which divides a gastrointestinal tract into compartments, wherein said compartment model describes gastrointestinal absorption of said prodrug molecule;
• and
• (b) a second compartment model which divides a body into plasma/blood and tissue compartments, wherein said compartment model describes the time course of the therapeutic agent, the nitric oxide donor, and nitric oxide in gastrointestinal tract, blood, and tissues;
• and
• (iii) generating output parameters from said pharmacokinetic model, wherein said output parameters determine the appropriateness of pairing of said therapeutic agent with said nitric oxide donor to create an effective prodrug molecule.

The prodrug molecule of claim 5 comprising:

• (i) a nitric oxide donor linked to an amino acid through a linkage that is susceptible to enzymatic hydrolysis or cleavage;
• and
• (ii) a therapeutic agent directly linked to said amino acid, or linked to said amino acid through a spacer, wherein the linkage between the therapeutic agent and the spacer, or the linkage between the spacer and the amino acid is susceptible to enzymatic hydrolysis or cleavage,
• wherein release of the nitric oxide donor and the therapeutic agent from the prodrug molecule can be controlled independently.

The prodrug molecule of claim 5 with the formula of:

• wherein R1 is the uncarboxylated core of a non-steroidal anti-inflammatory drug, or a structure of formula II:
• wherein R8 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, or an unsubstituted or substituted C3-12 branched chain alkyl;
• wherein X1 has a formula selected from the group consisting of:
• (i) formula III:
• wherein X2 is oxygen, sulfur, or NH, and X3 is oxygen, sulfur, or NH,
• (ii) formula IV:
• wherein X4 is oxygen, sulfur, or NH, and X5 is oxygen, sulfur, or NH,
• (iii) formula V:
• and
• (iv) formula VI:
• wherein X6 is oxygen, sulfur, or NH;
• wherein R2 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, or an unsubstituted or substituted C3-12 branched chain alkyl;
• wherein R3 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, or an unsubstituted or substituted C3-12 branched chain alkyl;
• wherein R4 is selected from the group consisting of:
• (i) hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl,
• (ii) formula VII:
• wherein R9 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, an amide derivative linked via a carboxy group of an amino acid, or an amide derivative of a polypeptide,
• (iii) formula VIII:
• wherein X7 is oxygen, sulfur, or NH, and R10 is an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl, and
• (iv) formula IX:
• wherein X8 is oxygen, sulfur, or NH;
• and R11 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• and R12 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• wherein R5 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, a structure of formula VIII, or a structure of formula IX;
• wherein R6 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII;
• wherein R7 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII, or a structure of formula XI:
• wherein X9 is oxygen, sulfur, or NH, and R14 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, or an amino acid wherein X9 is the amino group of the amino acid;
• and
• wherein Y is a structure of the formula XIII:
• or a structure of the formula XIV:
• wherein R15 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl.

The prodrug molecule of claim 14, wherein NR6R7 is a heterocycle of

• (i) formula X:
• wherein R13 is hydrogen, or
• (ii) formula XII:
• wherein R4 is selected from the group consisting of:
• (i) hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl,
• (ii) formula VII:
• wherein R9 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, an amide derivative linked via a carboxy group of an amino acid, or an amide derivative of a polypeptide,
• (iii) formula VIII:
• wherein X7 is oxygen, sulfur, or NH, and R10 is an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl, and
• (iv) formula IX:
• wherein X8 is oxygen, sulfur, or NH;
• and R11 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• and R12 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl.

The prodrug molecule of claim 5 with the formula of

• wherein Z is a structure of the formula XIII,
• or a structure of the formula XIV,
• wherein R15 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl;
• wherein R1 is the uncarboxylated core of a non-steroidal anti-inflammatory drug, or a structure of formula II:
• wherein R8 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, or an unsubstituted or substituted C3-12 branched chain alkyl;
• wherein R4 is selected from the group consisting of:
• (i) hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl,
• (ii) formula VII:
• wherein R9 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, an amide derivative linked via a carboxy group of an amino acid, or an amide derivative of a polypeptide,
• (iii) formula VIII:
• wherein X7 is oxygen, sulfur, or NH, and R10 is an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl, and
• (iv) formula IX:
• wherein X8 is oxygen, sulfur, or NH;
• and R11 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• and R12 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• wherein R5 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, a structure of formula VIII, or a structure of formula IX;
• wherein R6 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII;
• wherein R7 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII, or a structure of formula XI:
• wherein X9 is oxygen, sulfur, or NH, and R14 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, or an amino acid wherein X9 is the amino group of the amino acid;
• and
• wherein Y is a structure of the formula XIII:
• or a structure of the formula XIV:
• wherein R15 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl (an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl.

The prodrug molecule of claim 5 with the formula of

• wherein R1 is the uncarboxylated core of a non-steroidal anti-inflammatory drug, or a structure of formula II:
• wherein R8 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, or an unsubstituted or substituted C3-12 branched chain alkyl;
• wherein R4 is selected from the group consisting of:
• (i) hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl,
• (ii) formula VII:
• wherein R9 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, an amide derivative linked via a carboxy group of an amino acid, or an amide derivative of a polypeptide,
• (iii) formula VIII:
• wherein X7 is oxygen, sulfur, or NH, and R10 is an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl, and
• (iv) formula IX:
• wherein X8 is oxygen, sulfur, or NH;
• and R11 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• and R12 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• wherein R6 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII;
• wherein R7 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII, or a structure of formula XI:
• wherein X9 is oxygen, sulfur, or NH, and R14 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, or an amino acid wherein X9 is the amino group of the amino acid;
• and
• wherein Y is a structure of the formula XIII:
• or a structure of the formula XIV:
• wherein R15 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl.

The prodrug molecule of claim 5 with the formula of

• wherein R18 is selected from the group consisting of:
• (i) formula XVIII:
• (ii) formula XIX:
• (iii) formula XX:
• and
• (iv) formula XXI:
• wherein the substructure:
• represents the core structure of an amino acid selected from alanine, 2-aminobutyric acid, acid, α-aminosuberic acid, arginine, asparagines, aspartic acid, citrulline, β-cyclohexylalanine, cysteine, 3,4-dehydroproline, glutamic acid, glutamine, glycine, histadine, homocitrulline, homoserine, hydroxyproline, β-hydroxyvaline, isoleucine, leucine, lysine, methionine, norleucine, novaline, ornithine, penicillamine, phenylalanine, phenylglycine, proline, pyroglutamine, sarcosine, serine, threonine, tryptophan, tyrosine and valine;
• wherein R1 is the uncarboxylated core of a non-steroidal anti-inflammatory drug, or a structure of formula II:
• wherein R8 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, or an unsubstituted or substituted C3-12 branched chain alkyl;
• wherein R6 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII;
• wherein R7 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII, or a structure of formula XI:
• wherein X9 is oxygen, sulfur, or NH, and R14 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, or an amino acid wherein X9 is the amino group of the amino acid;
• and
• wherein Y is a structure of the formula XIII:
• or a structure of the formula XIV:
• wherein R15 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl.

The prodrug molecule of claim 5 with the formula of

• wherein R4 is selected from the group consisting of:
• (i) hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl,
• (ii) formula VII:
• wherein R9 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, an amide derivative linked via a carboxy group of an amino acid, or an amide derivative of a polypeptide,
• (iii) formula VIII:
• wherein X7 is oxygen, sulfur, or NH, and R10 is an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl, and
• (iv) formula IX:
• wherein X8 is oxygen, sulfur, or NH;
• and R11 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• and R12 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• wherein R5 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, a structure of formula VIII, or a structure of formula IX;
• wherein R6 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII;
• and
• wherein R7 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII, or a structure of formula XI:
• wherein X9 is oxygen, sulfur, or NH, and R14 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, or an amino acid wherein X9 is the amino group of the amino acid.

The prodrug molecule of claim 5 with the formula of

• wherein R4 is selected from the group consisting of:
• (i) hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl,
• (ii) formula VII:
• wherein R9 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, an amide derivative linked via a carboxy group of an amino acid, or an amide derivative of a polypeptide,
• (iii) formula VIII:
• wherein X7 is oxygen, sulfur, or NH, and R10 is an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl, and
• (iv) formula IX:
• wherein X8 is oxygen, sulfur, or NH;
• and R11 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• and R12 is a hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, or an unsubstituted or substituted heteroaryl;
• wherein R5 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, a structure of formula VIII, or a structure of formula IX;
• wherein R6 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII;
• and
• wherein R7 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, a structure of formula VII, or a structure of formula VIII, or a structure of formula XI:
• wherein X9 is oxygen, sulfur, or NH, and R14 is hydrogen, an unsubstituted or substituted C1-12 straight chain alkyl, an unsubstituted or substituted C3-12 branched chain alkyl, an unsubstituted or substituted C1-12 straight chain alkenyl, an unsubstituted or substituted C3-12 branched chain alkenyl, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted C1-4 aryl alkyl, an unsubstituted or substituted heteroaryl, or an amino acid wherein X9 is the amino group of the amino acid.