Prodrugs of Antiinfective Agents: A Review

- Purpose. Prodrugs are the pharmacologically inactive derivatives of active drugs typically intended to optimize the exposure of active drug at target site, through manipulation of its physicochemical, biopharmaceutical or pharmacokinetic properties. This approach has a number of advantages over conventional drug administration. Antiinfective agents are associated with number of limitations, responsible for their reduced bioavailability. Various antiinfective prodrugs have been synthesized with reduced side effects and improved pharmacological properties. The present paper illustrates different vistas of prodrug approach of antiinfective agents describing brief classification, synthetic approaches, pharmacological aspects and recent patents. It is a very productive area of research and its prologue in human therapy has given triumphant outcomes in improving the clinical and therapeutic effectiveness of drugs. This article is open to POST-PUBLICATION REVIEW . Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.


INTRODUCTION
Infection is the sequential event that starts from the invasion of pathogens in body tissues of host, followed by their multiplication, response of host tissues to these pathogens along with toxin produced by them (1). Scientific literature and medical experience indicate that microbial infection is one of the prime dangers to human life and World Health Organization considered it as leading cause of human death worldwide (2,3). As per available reports, infections caused by pathogenic viruses, bacteria, fungi and parasites account for millions of deaths per year (4,5).
The use of anti-infective agents are credited with saving more human lives than any other area of medicinal therapy discovered to date (6,7). Though antiinfective agents are being used for treatment of infectious disorders for last several decades, these are associated with some undesirable properties such as poor bioavailability, high first pass metabolism, toxicity, local irritation, incomplete absorption, poor aqueous solubility, lipophilicity, etc. as represented in Figure 1 (8)(9)(10)(11)(12).
Therefore, there is great emphasis on research to find out methods aimed at improving their desired characteristics [13][14][15]. The term "prodrug" or "proagent" was introduced by Albert to describe active pharmaceutical agents that undergoes biotransformation prior to elicit their pharmacological effects (16). Prodrug strategies consist of a transient modification of the physicochemical properties of a given compound through chemical derivatization. Such reversible chemical modification is designed to augment chemical stability, alter aqueous solubility, or improve bioavailability while the intrinsic pharmacological properties of the parent drug remain intact (17)(18)(19)(20)(21). A very good indication of the success of prodrug approach can be observed by examining the prevalence of prodrugs in the market.
Prodrugs are classified into carrier linked and bioprecursors on the basis of the way they release the active drug. Classification of prodrugs has been represented in Figure 2 (26)(27)(28)(29).  Figure 2. Classification of prodrugs Limitations associated with various antiinfective agents and successful implementation of prodrug approach for a variety of medicinally active agents has encouraged the researchers to synthesize prodrugs of antiinfective agents. A number of scientific papers have been published in last 3-4 decades. In this article, we have attempted to review the prodrugs of antiinfecive agents and summarize the triumph of prodrugs in achieving their improved pharmacokinetic parameters. This paper also discusses briefly general aspects of prodrug design and some recent patents of antiinfective prodrugs.

Prodrugs of Antibacterial Agents
Antibiotics are low molecular weight compounds produced by microorganisms and are active against pathogenic microorganisms (30). Treatment of infectious disorders depends upon several factors such as interactions among pathogens, facts related to host, physicochemical features of antimicrobial agents, its pharmacokinetics and pharmacodynamics. Infectious disorders caused by bacteria are the prime cause of mortality, affecting millions of people. Keeping in view the severity of these types of infections, continuous efforts for search of novel antibacterial agents are undertaken. In addition to search of novel antimicrobial agents, modification of existing drugs is a field of current and growing interest (31,32). Several attempts have been made to synthesize novel prodrugs of antibacterial agents.
Prodrug approach has been adopted for synthesis and evaluation of a series of amino acid and dipeptide prodrugs of IMB-070593, 1 by Zhang et al. Due to greater water solubility, compounds 2 and 3 were found to exhibit 1.19-1.50 fold high antibacterial activity against methicillin-sensitive S. aureus and S. pneumonia than the parent drug (28). New derivatives of ceftazidime as possible prodrug were synthesized by Alwan et al. The compounds 4 and 5 showed reasonable antibacterial activities against G (+) Streptococcus species in comparison with ceftazidime, having no activity against these types of microorganisms (33). Prodrug approach was adopted using diglyceride as a promoiety to improve bioavailability of poorly absorbed drug, norfloxacin; a second generation fluoroquinolone antibacterial by Dhaneshwar et al. The prodrug 6 has been synthesized by standard procedures using dipalmitine as a carrier and found to exhibit improved pharmacological profile than the parent compound at equimolar dose that indirectly indicated improved bioavailability (9 Dubey et al have synthesized and evaluated various novel aromatic and aliphatic esters of metronidazole to improve the physicochemical properties (Rm values, lipophilicity) using prodrug approach. The synthesized compounds 7 and 8 were found to be more potent in terms of MIC (μg/mL) against C. Perfringens in comparison to metronidazole due to enhanced lipophilicity (10) Abdul-Kadir et al prepared cyclic amine derivatives of metronidazole using acetate spacer. These derivatives showed better physicochemical and biological properties. As per studies, the compound 9 can be utilized on its own as effective mutual prodrug without requirement of any drug in connection (34)

9
Dibama et al carried out drug release studies and investigated antibacterial behavior of a watersoluble nalidixic acid/calix [4]arene ester adduct 10. In vitro antibacterial evaluation showed that the title compound was efficient on one Gram-negative (E. coli) and two Gram-positive (S. aureus) reference strains, with a clear gain of activity when compared to its two hydrolysis by-products (11).
Sobczak et al developed and carried out structural analysis of polyester prodrugs of norfloxacin. The two, three and four arm star shaped poly(ε-caprolactone) and poly(D,L-lactide) homopolymers and copolymers of ε-caprolactone with D, L lactide were used for synthesis of norfloxacin polyester prodrugs. The synthesized polyester prodrugs, 11 were proved to be good potential candidates to be used as drug delivery carriers (35). Yar et al synthesized macromolecule conjugate of hydroxypropyl methacrylamideofloxacin, 12. They found that covalent linkage of ofloxacin to a biocompatible polymer, poly (hydroxypropyl methacrylamide), via the ester group leads to a delivery system which is capable of releasing the drug in a sustained manner over the gastrointestinal tract and ultimately increased t 1/2 of the drug (36

12
Isoda et al synthesized various prodrug esters and carried out their pharmacokinetic studies. Oral carbapenem antibiotic L-084, 13 was found to exhibit high bioavailability and C max in humans. Compound 13 showed a strong antimicrobial activity against Gram-positive and Gram-negative bacteria and exhibited the highest intestinal absorption among synthesized prodrugs of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[1-(1,3-thiazolin-2-yl) azetidin-3-yl] thio-1-carbapen-2-em-3-carboxylic acid (37). were found to be more effective as compared to cefepime, an antibacterial drug existing in market, at the equivalent concentration. The compound 16 and 18 had antifungal activity in vitro almost comparable with fluconazole, the most accepted antifungal drug. The escalated activity of these bioconjugates compared to the parent molecule, curcumin may be due to improved cellular uptake or reduced metabolism of these bioconjugates resulting in building up of enough concentration inside the infected cells (39

31
Mori et al designed and developed a novel prodrug 31, AS-924, by esterifying ceftizoxime with a lipophilic pivaloyloxymethyl (POM) group and introducing a water soluble L-alanyl group. As AS-924 was found to have a good balance of lipophilicity and water solubility, it could be clinically expected that the synthesized prodrug, when administered orally, would be absorbed well and consequently show good clinical efficacy (42).
Wei et al synthesized 5'-dipeptidyl derivatives of 5-fluorodeoxyuridine (FdU), 32-35. These prodrugs were found to be biologically inactive but could be activated by peptide deformylase. Because the deformylase is ubiquitous among bacteria but absent in mammalian cells, these prodrug compounds provided a novel class of potential antibacterial agents (43).   The antibacterial activity of these esters was found to be comparable to that of metronidazole (45).

Prodrugs of Antitubercular Agents
Tuberculosis is one of the major public health concerns globally, caused by Mycobacterium tuberculosis (46). It has been reported by WHO that 9 million people suffered illness and 1.5 million died due to tuberculosis in year 2013 alone (47).
In recent years, tuberculosis is on the increase principally due to HIV infection, immigration, increased trade and globalization (48). Therefore, it is an urgent task to develop new derivatives or formulations of antitubercular drugs acting on novel drug targets to enhance stability, half life as well as oral bioavailability.
Fernandes et al synthesized pyrazinoic acid prodrug, 2-chloroethyl pyrazinoate, 46 and evaluated it for its activity in Mycobacterium tuberculosis H 37 Rv (ATCC27294) in minimal inhibitory concentration (MIC) assay using the microplate Alamar blue assay technique. The obtained MIC of the synthesized prodrug was found to be 3.96 g/mL, proved better than pyrazinamide (reported MIC 50-100 g/mL) (49).
Several alkyloxycarbonyloxyalkyl ester prodrugs of meropenem were synthesized and evaluated in an effort to improve the lipophilicity as well as oral absorption of the parent carbapenem by Teitelbaum et al. Their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The prodrugs containing the 2-benzosuberyl, 2-tetralyl, and 2-indanyloxycarbonyloxymethyl promoieties, 47-49 respectively were found to be significantly more stable at physiological pH 7.4 and intestinal pH 6.0. In simulated gastric fluid (pH 1.2), these compounds degraded to form the ring-opened prodrug metabolite (50). Cassano et al synthesized, characterized and carried out in vitro antitubercular activity of isoniazid-gelatin conjugate, 50. Spectrophotometric analysis revealed that the protein derivative was an excellent isoniazid prodrug since there was a 40% reduction in release of toxic metabolites (isonicotinic acid) by the prodrug and the compound 50 showed significant antitubercular activity (12). Meng et al reported a novel series of prodrugs of SQ109, 60. The parent drug, 60 released from the synthesized prodrug, 61 after oral administration exhibited preferential tissue distribution into lung and spleen, the target organs of tubercular infection and replication (53). Roseeuw et al carried out synthesis, degradation and studied antimicrobial properties of targeted macromolecular prodrugs of norfloxacin. In Gly-Phe-Gly-Gly (α-norfloxacin)-OMe, 64 norfloxacin was linked to the carrier through an alpha bond. They demonstrated that targeting by using mannose as a homing device was required to achieve antimycobacterial activity in vivo (55). Cycloserine (seromycin, 4(R)-amino-3isoxazolidinone), a well-known drug used for the treatment of tuberculosis and certain genitourinary infections, especially when caused by Enterobacteria or E. coli. Systemic side effects check the usage of cycloserine and topical application or local delivery has restricted value because cycloserine is a highly water-soluble compound and inadequately permeable through lipophilic membranes such as the skin. Thorsteinsson et al synthesized various 4,5dihydroisoxazol-3-yl fatty acid ester derivatives of cycloserine, 65-68 to improve skin permeation of cycloserine. The ester derivatives were synthesized using the tert-butoxycarbonyl (t-Boc) protection strategy. The skin permeation of cycloserine across the hairless mouse skin was reported to increase up to 20-fold by the fatty acid esters (56).

Prodrugs of Anitmalarial Agents
Malaria is a potentially lethal tropical disorder, spread by mosquitoes and its causative agent is protozoan parasites of the genus Plasmodium. According to latest estimates, approximately 198 million cases of malaria and 5,84000 deaths due to this diseases were observed globally in 2013 (57,58). New antimalarial compounds, particularly those based on compounds structurally unrelated to existing antimalarial drugs with new mechanisms of action or prodrugs of existing compounds with modified physicochemical characteristics/ pharmacokinetic parameters are urgently needed. Davanço et al prepared and evaluated the antimalarial activity along with toxicological profile of a novel dipeptide primaquine prodrug (Phe-Ala-PQ) using in vitro and in vivo assay. The prodrug was found to be more soluble in water, effective against sporogenic cycle and less toxic in a monkey kidney cell line (BGM) and human hepatoma cell line (HepG2) than the parent drug primaquine (59).
Milner et al synthesized few metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen (WR621341), 69 the de-methylated metabolite of ketotifen, was found to be 15 and 8 fold more potent against Pf D6 and Pf W2, respectively, which are the two most susceptible strains of Plasmodium falciparum. They observed no toxicity with the metabolite WR621341, 69 even when dosed as high as 320 mg/kg for 3 days (60).
Caldarelli et al reported the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276), 70, a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. After oral administration, the cyclic disulfide prodrug 71, showed the best improvement of oral efficacy in comparison to the parent drug (61

71
Dubar et al carried out the synthesis, antiparasitic evaluation and docking studies of ester prodrugs of ciprofloxacin as DNA-gyrase inhibitors. The synthesized compound 72 was found to be more active as compared to ciprofloxacin, its ethyl ester prodrug, 73 and the dual mettallocenic/prodrug, ferrocenyl derivative of ciprofloxacin, 74 against P. falciparum as well as T. gondii (62).
Dubar et al in their previous studies reported the enhancement of the antimalarial activity of ciprofloxacin using a double prodrug/ bioorganometallic approach. Two new achiral compounds 73 and 74 were found to be 10 to 100 fold more active than ciprofloxacin against Plasmodium falciparum chloroquine susceptible and chloroquine-resistant strains (63). Chambel et al synthesized the imidazolidin-4ones, 79-89 as potential pro-prodrugs of the antimalarial primaquine. These compounds were designed with the aim of reducing the metabolic inactivation pathway of primaquine that involves oxidative deamination at the primary amino group. It also diminishes the blood toxicity induced by primaquine particularly its ability to provoke oxidation of oxyhemoglobin to methemoglobin. These compounds were found to be convincingly stable compounds, hydrolyzing to the consequent amino acid derivatives, 90 in pH 7.4 buffer at 37°C with half-lives ranging from 9 to 30 days (66

93
Vial et al synthesized neutral antimalarial prodrugs that deliver bisthiazolium compounds with antimalarial activity in the nanomolar range. These compounds were found to be suitable for both parenteral as well as oral use and plasma promotes rapid conversion of the prodrug into the parent drug. Oral administration of the TE3 prodrug, 94 was found to entirely cure Plasmodium cynomolgi infection in rhesus monkeys (68). Vangapandu et al reported antimalarial activities of N 8 -(4-amino-1-methylbutyl)-5-alkoxy-4-ethyl-6-methoxy-8-quinolinamines and their pro prodrug analogues synthesized by covalently connecting them to the redox-sensitive and esterase-sensitive linkers via the amide linkage. Synthesized analogues were evaluated for in vivo blood-schizontocidal activity as potential pro prodrug models for the primary amino group containing 8-quinolinamines.The most effective pro prodrug analogue, 95 displayed potential activities against drug-sensitive and drug-resistant strains of Plasmodia in vivo (69

Prodrugs of Antiviral Agents
Viral infections are considered one of the principle threats to human life and health worldwide (74). Dong et al reported a new alkoxyalkylphosphodiester prodrug of ribavirin, designed to release the active ribavirinmonophosphate species selectively in nucleated cells while limiting its exposure in anucleated red blood cells (RBCs). Prodrug 100 was found to display enhanced in vitro antiviral activity against the hepatitis C virus replicon and influenza virus. These results indicated that synthesized prodrug was found to have the potential for safer, lower, less common and consistent administration than ribavirin (75). Hiramath et al synthesized and carried out in vitro and bioavailability studies of acyclovir prodrug. The macromolecular prodrug of acyclovir was synthesized by coupling the drug to PEG which was then polymerized to get polymeric prodrug, 102. The delayed release of free drug from the conjugate resulted in longer retention time in plasma and was found to have higher bioavailability of acyclovir from the PEG conjugate (77).

118
Tang et al synthesized a series of ester analogues of acyclic nucleotide adefovir and tenofovir as potent antiviral agents. The antiviral evaluation results indicated that bis benzyl ester prodrug of adefovir, 119 and bis allyl ester prodrug of tenofovir, 120 exhibited potent antiviral activities (81).

127
Song et al described the synthesis of amino acid ester prodrugs of the antiviral agent 2-bromo, 5-6 dichloro-1-(β-D-ribofuranosyl) benzimidazole and carried out evaluation of these compounds to check their efficiency as potential substrates of hPEPT1 transporter. These ester prodrugs, 128-139, were found to have 2-4 fold higher affinity for hPEPT1 compared to 2-bromo,5-6 dichloro-1-(β-Dribofuranosyl) benzimidazole (83). A dipeptide prodrug of the antiviral nucleoside acyclovir (ACV), val-val-ACV (VVACV), was developed and evaluated in vivo as a potential drug candidate for improving antiviral efficacy against herpetic epithelial and stromal keratitis by Anand et al. VVACV, the dipeptide prodrug of ACV, 103 was found to be highly soluble, stable in water, significantly less cytotoxic than parent drug and allowed formulation into 1% to 3% eye drops. In vivo, VVACV 140 exhibited excellent antiviral activity against epithelial and stromal keratitis in the rabbit eye model (84

140
Yang et al carried out chemical stability, enzymatic hydrolysis and nasal uptake studies of amino acid ester prodrugs of acyclovir. They found that the L -aspartate β-ester prodrug, 141 could be absorbed nasally and was proved to be least labile to enzymatic hydrolysis in the nasal mucosa (85). were proved to be almost as active as acyclovir, 103 and got readily hydrolyzed to release the parent compound (87 [88]. According to the statistical facts on the AIDS, outbreak of epidemic provided in 2013 by WHO, there were suspected cases of about 35 million people having HIV infection and 1.5 million deaths due to this disorder [89,90]. HIV acquires resistance to all presently accessible drugs, resulting in swiftly decreased drug effectiveness. There is incredible potential for improving anti-HIV therapy not only by increasing the potency of antiviral drugs, but also by reducing the burden of the dosing regimen. This can be achieved by modifying the physicochemical, biopharmaceutical and pharmacokinetic properties of drug through the development of prodrugs (91).
Agarwal HK et al synthesized three fatty acyl conjugates of emtricitabine as nucleoside prodrugs and evaluated these prodrugs against various strains of HIV-1. Due to improved lipophilicity and better cellular uptake the compound myristoylated conjugate of emtricitabine, 148 was proved to be a more effective analogue with a better resistance profile compared to its parent compound (92).

152
Agrawal et al designed and evaluated prodrug of zidovudine by coupling it to 2-hydroxymethyl methacrylate through a succinic spacer to get a monomeric drug conjugate which was polymerized to obtain the polymeric prodrug. Poly (HEMAzidovudine) conjugate, 153 was found to exhibit improved pharmacokinetics as compared to parent drug zidovudine, 154 by increasing its short life and bioavailability resulting in less frequent administration and decreased toxicity (95).

154
Li et al described the synthesis of S-acyl-2thioethyl (SATE) prodrug of 2' modified 5' noncarbocyclic adenine analogue and tested these prodrugs for antiviral activity. As the ionic character of a phosphonic acid presented an obstacle for cellular permeability, S-acyl-2thioethyl masked these charges with neutral groups to form more lipophilic derivatives capable of crossing the gastrointestinal wall and reverted back to the parent nucleoside phosphonic acid. SATE prodrug, 155 was found to exhibit 4 fold higher anti-HIV activity compared to parent compound (96). Nanoparticles of compound 156 were prepared by the process of ionotropic gelation using tripolyphosphate to augment the delivery to viral reservoirs of HIV. On comparing the data of chitosan-O-isopropyl-5'-O-stavudine monophosphate conjugate and stavudine-loaded nanoparticles, in vitro drug release studies revealed that the crosslinked conjugate nanoparticles can prevent the coupled drug from leaking out of the nanoparticles in blood circulation and provide a mild sustained release of stavudine 5'-(O-isopropyl) monophosphate without the burst release (97). To improve the pharmacological properties as well as pharmacokinetic profiles of the current protease inhibitors (PIs) and consequently therapeutic potential, Roche et al reported the synthesis of PI-spacer-valine prodrugs (PIsaquinavir, indinavir and nelfinavir). They evaluated these synthesized prodrugs for in vitro stability with respect to hydrolysis, anti-HIV activity, cytotoxicity and permeation through a monolayer of Caco-2 cells as compared with their parent PIs and first generation of valine-PIs. They found that PI-spacer-valine prodrugs, 160-164 proved to be chemically more stable than the first generation PI-Val prodrugs with respect to hydrolysis (99). Hamada et al designed and synthesized water-soluble prodrugs of KNI-727, 177 a potent small-sized dipeptide-type HIV-1 protease inhibitor consisting of an Apns-Dmt core (Apns; allophenylnorstatine, Dmt; (R)-5,5-dimethyl-1,3thiazolidine-4-carboxylic acid) as inhibitory machinery and carried out its kinetic studies. The synthetic prodrug, 178 was found to exhibit improved water-solubility (13mg/mL) more than 8000-fold in comparison with the parent compound, 177 resulted in improved oral absorption and bioavailability (102).

178
Miazga et al presented the novel synthesis of 2',3'-dideoxy-3' fluoro-2-thiothymidine (S 2 FLT) based on transformation of appropriately protected 1-β-D-threo-ribofuranosylthymine. 179 and 180 were found to be most potent inhibitors of HIV-1 and exhibited ten times higher anti-HIV-1 activity and higher therapeutic index than their mother nucleoside S 2 FLT (103). Ind-Oleyl, 196 displayed both a high inhibitory level and high chemical stability. No cytotoxicity was detected for these synthesized prodrugs for concentration as high as 10 or even 100 µM (106 Machado et al studied antiviral activity and resistance profile of phosphazid, a novel prodrug of zidovudine. This prodrug was found to have a higher selective index than the parent drug (107).

Prodrugs of Antifungal Agents
Fungal pathogens are a major public health threat with significant global effects which, surprisingly, are not being addressed as they should. These pathogens are widely distributed in soil, plant debris and other organic substrates (108). Fungal infections are caused by these microscopic organisms that can invade the epithelial tissue. Especially in the developed countries fungal infections have grown rapidly in last few decades and proved to be a significant cause of morbidity and mortality despite advances in medicinal chemistry. For the treatment of opportunistic fungal infections, the development of new potent or structural modification of the already available antifungal drugs is an important challenging task for modern medicine, with a potent, broad spectrum of antifungal activity, good pharmacokinetics and excellent bioavailability.
A number of prodrugs have been synthesized to combat the severity of fungal infections. Few of them are mentioned here. To improve the aqueous solubility of an itraconazole analogue YL-24, 200, Liu et al synthesized a series of novel prodrugs and carried out its in vivo antifungal activity. The phosphate disodium salt compound 201, among these prodrugs, exhibited excellent aqueous solubility (9.8 mg/mL) at near-neutral pH, adequate stability in buffer solutions, as well as complimentary pharmacokinetic profiles (107). Kagoshima et al described the synthesis and evaluation of a number of novel water soluble ester prodrugs of antifungal triazole CS-758. Compound 202 was found to have good water solubility (>30 mg/mL), consequently proved to be a promising antifungal agent for parenteral use (108).
Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs was described by Ueda et al. Both derivatives exhibited high solubility in water and transformed to the parent compound in presence of alkaline phosphatase, as well as in vivo. BMS-379224, 203 has proved to be one of the most promising prodrug and has now advanced to its clinical study as an intravenous formulation of parent compound, ravuconazole 204 (109). This synthesized prodrug was found to exhibit high chemical stability and water solubility along with strong antifungal activity against systemic candidiasis and aspergillosis (110). In previous study Ohwada et al synthesized water soluble N-benzyltriazolium or Nbenzylimidazolium salt type prodrugs of many highly lipophilic triazole or imidazole antifungals. The prodrug 206 was found to have sufficient chemical stability as well as water solubility for parenteral use. It showed rapid and quantitative transformation to the active substance in human plasma (111).

206
Sun et al carried out synthesis and evaluation of various N-acyloxymethylcarbamate linked prodrugs of 3-amido pseudomycin analogues. These synthesized combinations, 207-210 demonstrated improved toxicity profiles in comparison to their corresponding 3-amides as well as the parent pseudomycin B. They were found to exhibit good in vivo efficacy against murine candidiasis (112).
In another study Sun et al described the synthesis, bioconversion, antifungal activity, in addition to preliminary toxicology evaluation of a series of N-acyloxymethyl carbamate linked triprodrugs of pseudomycins. Two pseudomycin triprodrugs 211, 212 showed excellent in vivo efficacy against systemic candidiasis (113).

RECENT PATENTS
Over the past few decades, number of patents has been issued in the field of anti-infective agents encompassing a range of drugs having various activities. The patents described in Table 2 reveal information related to various features, salient approaches and advancements of antiinfective agents.

FUTURE PROSPECTS
Prodrugs of antiinfective agents can present an attractive option to improve undesirable properties of a wide variety of these drugs without losing the benefits of the parent drug molecule. Nonetheless, developing a prodrug of these available antimicrobial agents can still be more feasible, economical and faster strategy than searching for an entirely new therapeutically active agent with suitable ADME (absorption, distribution, metabolism and excretion) properties. Hence, antiinfective prodrugs are becoming an essential element of drug discovery paradigm, as illustrated by the increasing number of its approved prodrugs and patents. Moreover, the development of novel and highly efficacious antimicrobial prodrugs and their preface in clinical therapy would be much fruitful in forthcoming years.

CONFLICT OF INTEREST
The authors have declared no conflict of interest.