Prodrug design is productive approach for drug targeting by switching the biopharmaceutical, physiochemical or pharmacokinetic properties. Prodrugs, are active therapeutic chemical agent, which must undergo modification in vivo to release the active drug [1,2].

Design of Prodrug

Prodrug are compounds, which are inactive but are converted in the body to the active drug:

• Acid sensitivity

• Poor membrane permeability

• Drug toxicity

• Bad taste

• Short duration of action

• Two things are needed to consider when designing prodrugs

• To ensure that the prodrug is effectively converted to the active drug once it is absorbed into the blood supply

• To ensure that any groups cleaved from the molecule are non-toxic [3,4]

Prodrugs have become an initiated idea and a strong tool in developing the pharmacologically potent structures and get the better of pharmaceutical, physiological and biopharmaceutical barriers to a drug's functionality [5].

• Barrier linked to the physicochemical properties of drug

• Barrier in the pharmacokinetic phase

The poor drug effects such as toxicity, stability, permeability, solubility, drug targeting are genuine challenges for the fortunate growth and commercialization of drug molecules, this can be attain through physical, chemical or biological ways [6,7].

Figure 1: Comparison Between Prodrugs and Active Drugs

The biological approach is to alter route of administration which may or may not be allowable to patient. The physical approach is to adjust the plan of dosage form such as controlled delivery of drug. The third and the finest way in increasing drug selectivity while keeping down toxicity, is the chemical approach for design of prodrugs [8,9].

Functional group derivative involved in prodrug approach:

• NH2

• Amine

• Alcohol

• COOH

• Carboxylic acid

Functional group compliant to prodrug design:

Factors should be examined when designing a prodrug

• Parent drug-which functional group are manageable to chemical prodrug derivation

• Pro moiety-ideally be safe and rapidly excreted from the body

• Parent and prodrug-ADME and pharmacokinetic properties need to be comprehensively known

Esters as prodrugs of carboxyl, hydroxyl and thiol functionalities

• Esters are common most prodrug used, round about 49% of all marketed prodrugs start up by enzymatic hydrolysis

• Esters mainly used to enhance lipophillicity

• Passive membrane permeability of water soluble drugs by disguise charged groups such as carboxylic acids and phosphates

• Readily hydrolyzed by esterase found in blood, liver and other organs including, carboxyl esterase, acetylcholinesterase, butrylcholinesterases

Carbonates and Carbamates as prodrugs of carboxyl, hydroxyl or amine functionalities:

• These are different from esters by the existence of an oxygen or nitrogen of carboxyl carbon on both sides

• These more stable than esters but more susceptible to hydrolysis than amides. Carbonates are derivative of carboxylic acid and alcohols and carbamates are carboxylic acid and amine derivatives

• Bioconversion of many carbonate and carbamates prodrugs require

Amides as Prodrugs of Carboxylic Acids and Amines

In prodrug design, amides been used only to limited range owing to their relatively high enzymatic stability in vivo. Carboxylesterases, peptidases or proteases usually hydrolyses amide bond.

Figure 2: Representative Chemical Structures of Selected Prodrugs and Their Functional Modifications

Figure 3: Schematic Representation of Prodrug Formation, Barrier Transport and Subsequent Enzymatic/Chemical Conversion

Table 1: Prodrug Approaches for Overcoming Limitations of Parent Drugs and Their Therapeutic Applications

PROBLEMS	PARENT DRUG	PRODRUG	How it is solving the problem	Therapeutic use
GI Irritation	Salicylic Acid	Aspirin	Increased stimulation of acid secretion or by interference   With protective mucosal layer.	Reducing fever, relieve mild to moderate pain.
Odour	Ethyl mercaptan	Pthalate ester	ethyl mercaptan is foul smelling liquid at BP(35 degree celsius) is converted into its pthalate ester (high BP and odorless)	treatment of Leprosy
Taste	Chloramphenicol	Palmitate ester	two approaches; a) reduction of drug solubility in saliva b) lower the affinity of drug towards taste receptor	antibiotic (mainly eye infections)
	Clindamycin	Palmitate ester	two approaches; a) reduction of drug solubility in saliva b) lower the affinity of drug towards taste receptor	Bacterial infections
Physical form of drug	Ethyl mercaptan	1,3-diester	ethyl mercaptan is liquid drug and converting of such liquid drug in solid prodrug  involves formation of symmetrical molecule having higher tendency to crystallize	manufacturing of fungicides and bacteriocides
Low aqueous solubility	Dexamethasone	Hemisuccinates and phosphates	Dexamethasone, because of their low water solubility generally administered in the  form of water soluble esters as hemisuccinates and phosphates.	used at higher doses for emergency treatment or other life threatening situations.
	Mitindomide	Fetindomide	Mitindomide, poor solubility in water and in most pharmaceutically acceptable solvents. Prodrug was designed so that mitindomide would be release in vivo by the loss of two molecules of phenylalanine and formaldehyde. Observed that in vitro formaldehyde exerts a catalytic effect on fetindomide hydrolysis.	Anti - tumor agent
Chemical stability	Azacytidine	Bisulfite prodrug	The aqueous solution of azacytidine is readily hydrolized but bisulfite prodrug is stable to such as degradation at acidic pH and more water soluble than parent drug. The prodrug converts to the active drug at the physiological pH of 7.4	Anti-neoplastic agent

Oximes as Derivatives of Ketones, Amidines and Guanidines

Oximes (for example, guanidoximes, ketoximes, amidoximes) are derivatives of guanidines, ketones and amidines, thus providing a chance to modify molecules that lack of carboxyl, hydroxyl, or amine functionalities.

The present review is a try to collect and confront available information on the subject. Some basic problems, however, been left untouched. For example, for extrapolation of data the difficulty from animals to humans come across during toxicologic and toxicokinetic studies with drugs is added with prodrugs because not only might the metabolism difference of the active moiety , but also its availability from the prodrug. As a matter of fact, there is currently no published rationale for the management of animal and human pharmacokinetic programs during development and pro drug research. Although the prodrug point of view it is advancing and reaching successes in providing effective medications to a variety of diseases it still needs the utilization of the sophisticated computational methods used for the design of drugs. Kinetics and thermodynamics for biological systems (active sites of receptors and enzymes and etc.) that have biomedicinal interests have been intensively researched and have been proved to be fruitful. Today, quantum mechanics, such as ab initio, semi-empirical and Density Functional Theory (DFT) and Molecular Mechanics (MM) including docking are increasingly being utilized to characterize active sites of receptors and enzymes. These widely used methods have proven as successful tools for providing structure-energy calculations for an accurate prediction of potential drugs. This plan might help substances too toxic, or impotent to show adequate pharmacologic effects in their basal form to go through primary and secondary screening, before successfully reaching human testing. It is evident that if such an approach were to become an integral part of basic drug design and not just a hindsighted attempt to solve problems associated with older drugs, it would also be necessary to develop new biopharmaceutical and pharmacokinetic approaches to tackle the new challenges.

1. Brahmankar D.M. and S.B. Jaiswal. Biopharmaceutics and Pharmacokinetics: A Treatise. Vallabh Prakashan, 1995, pp. 162–168.

2. Singh H. and V.K. Kapoor. Medicinal and Pharmaceutical Chemistry. 2nd ed., Vallabh Prakashan, 2005, pp. 264–280.

3. Abraham, Donald J., editor. Burger’s Medicinal Chemistry and Drug Discovery. 6th ed., vol. 2, Wiley, pp. 501–512.

4. Patil S.J. and P.J. Shirote. “Prodrug approach: An effective solution to overcome side-effects.” International Journal of Medical and Pharmaceutical Sciences, 2011, pp. 1–13.

5. Verma et al. “Prodrug as a chemical delivery system: A review.” Asian Journal of Research in Chemistry, 2009, pp. 75–100.

6. Roche E.B. American Pharmaceutical Association—Academy of Pharmaceutical Sciences Symposium. Washington, DC, 1977.

7. Balant L.P. and J. McAinsh. “Concepts in drug metabolism.” Edited by P. Jenner and B. Testa, Marcel Dekker, 1980, p. 311.

8. Peppercorn M.A. “Sulfasalazine: Pharmacology, clinical use, toxicity and related new drug development.” Annals of Internal Medicine, vol. 101, no. 3, 1984, pp. 377–386.

9. Karaman R. Prodrugs Design: A New Era. Nova Science Publishers, 2014.