Medicinal Chemistry - Volume 8, Issue 4, 2012

Selective chemical functionalization of cyclodextrins (CDs) is a readily amenable methodology to produce amphiphilic macromolecules endowed with modulable self-organizing capabilities. Herein, the synthesis of well-defined amphiphilic CD derivatives, with a “skirt-type” architecture, that incorporate long-chain fatty esters at the secondary hydroxyl rim and a variety of chemical functionalities (e. g. iodo, bromo, azido, cysteaminyl or isothiocyanato) at the primary hydroxyls rim is reported. Nanoprecipitation of the new CD facial amphiphiles, or binary mixtures of them, resulted in nanoparticles with average hydrodynamic diameters ranging from 100 to 240 nm that were stable in suspension for several months. The precise size, zeta potential and topology of the nanoparticles are intimately dependent on the functionalization pattern at the CD scaffold. Highly efficient molecular encapsulation capabilities of poorly bioavailable drugs such as diazepam (DZ) were demonstrated for certain derivatives, the drug release profile being dependent on the type of formulation (nanospheres or nanocapsules). The efficiency and versatility of the synthetic strategy, together with the possibility of exploiting the reactivity of the functional groups at the nanoparticle surface, offer excellent opportunities to further manipulate the carrier capabilities of this series of amphiphilic CDs from a bottom-up approach.

In the present work, a promising formulation of an inhaled powder based on tobramycin-loaded microparticles has been reported. Biodegradable microparticles with controlled diameters in the range of 1-5 μm and narrow size distribution were synthesized by Flow Focusing® technology. Particles production was planned and optimized with the aid of a well-established mathematic model. Close agreements between theoretical an experimental sizes were obtained. To deliver a high payload of tobramycin to the lungs, the influence of surfactant concentration, polymer-drug ratio and initial drug concentration were investigated. For chosen formulations, drug delivery profiles were also studied. In some cases, it was found a controlled drug delivery for more than ten days, which could represent an important advance in the treatment of chronic lung infections. Other particles factors affecting deposit of an aerosol in the lung were also studied, such as surface charge and density.

Lipid nanoparticles loading the sunscreen 2,4-dihydroxybenzophenone (DHB-LNPs) have been prepared by high-pressure homogenization and ultrasound techniques. The combination of both methodologies improves the entrapment efficiency percentage reaching 95%. The morphology of the DHB-LNPs was studied with scanning electron microscopy (SEM) and atomic force microscopy (AFM), while the surface and interior chemical composition was analyzed by X-ray photoelectron spectroscopy (XPS) at different irradiation times. Conductivity of aqueous dispersions of the DHBLNPs was determined by impedance spectroscopy. A possible DHB-LNPs application related to drug release in a system simulating skin-properties is shown.

Calcium is essential to homeostasis and functioning of multiple organ systems. Its circulating concentration is maintained within a very tight physiologic range: 2.25 and 2.50 mmol/L. Under physiological conditions, the ionized calcium concentration is regulated by the parathyroid hormone (PTH), and 1,25(OH)2 vitamin D through interactions on target organs such as kidney, bone and intestine. In mild, moderate, and severe hypercalcemia, laboratory findings are essential in assessing and monitoring disease course and therapy. The main tools are specific standard biochemical tests able to assess calcium balance and renal function, and some specific biochemical tests, such as PTH, 25(OH) vitamin D, and genetic sequencing, used to clarify the cause of hypercalcemia and, subsequently, to determine appropriate therapy. Once hypercalcemia is confirmed by ionized calcium measurement, the intact PTH assay plays a crucial role to differentiate PTH-mediated from non-PTH-mediated hypercalcemia. Mild hypercalcemia is also present in up to 10-20% of patients treated with lithium for bipolar disorders, in 7-8% of those treated with thiazide diuretics, and in patients with prolonged immobilization, while very high (>3.5 mmol/L) serum calcium levels, together with low PTH, and a rapid increase of hypercalcemia, usually suggest a malignancy-associated hypercalcemic syndrome. The measurement of PTH-related protein, a tumor product that mimics certain action of PTH, is useful only in selected cases. The role of biochemical markers of bone turnover for predicting metastatic bone disease, and monitoring bone metabolic changes, and their usefulness as a predictive mean of the likelihood of bone loss or fractures risk is still unclear.

Hypercalcemia is a relatively frequent alteration, mostly associated to primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH). Treatment first includes rehydration and loop diuretics, as general measures. Bisphosphonates are considered the drugs of choice due to their long-term management. Calcitonin is preferable in the short-term control of severe hypercalcemia. The antireabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Zoledronate is superior to both clodronate or pamidronate in the treatment of MAH. Calcimimetic agents has been recently introduced to control hypercalcemia in selected cases of PHPT. They are used when surgery is not possible or patients do not meet surgical criteria. Malignancy- associate hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic MAH. The first concerns the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). Recently a humanized monoclonal antibody against human PTHrP has been generated and is still under evaluation. The receptor activator of nuclear factor-κ ligand (RANKL) has a critical role in the etiology of malignancy skeletal complications. The fully humanized anti-RANKL antibody (denosumab) would seem to be even more effective than bisphosphonates to suppress bone resorption, as shown in preliminary results .

Acute hypercalcemia is a life-threatening rather rare condition. This condition may represent an acute decompensation of a pre-existing hypercalcemia, or may be acute at the first instance of the electrolyte disturbance. Hypercalcemic patients can present with a broad spectrum of symptoms, but most of them are mild and non-specific. Hypercalcemia affects a group of organs, which are considered together as a syndrome. The supportive care and ABC assessment are the first step to preserve vital functions. Severity index criteria should be considered at admission: severe dehydratation, mental status alteration, renal impairment, cardiac arrhythmias, ionized calcium level, nausea or vomiting, low social level. The neurological status and the main parameters (arterial blood pressure, cardiac pulses, oxygen saturation, temperature) must be monitored in all patients. Five keystones in the treatment of the hypercalcemic crisis should be considered: (1) Restore normovolemia to prevent renal impairment, (2) Restore renal function and enhance renal excretion of calcium, (3) Dialysis, (4) Inhibit osteoclastic bone resorption, and (5) Reduce intestinal calcium absorption. Currently, bisphosphonates are the drugs of choice in most of the patients after adequate hydration, while non-bisphosphonates drugs, such as calcitonin, gallium nitrate and mithramycin, are now rarely used. It is pivotal to recognize and treat the disease, according to evidence-based guidelines. At the same time, a short diagnostic program should be started to focus to the appropriate treatment of the underlying disease.

The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs.

In order to develop a new series of dual inhibitors of SRC and ABL, and to investigate whether the pyrimidin- 4-ylamino moiety is critical for dasatinib’s activity, acetyl substitution was adopted as alternate scaffold at the 2-amino group. Eighteen novel dasatinib derivatives were developed by a parallel synthesis approach and evaluated for their antiproliferative effects. Preliminary tests showed that some of the target compounds IId, IIe and IIf manifested strong antiproliferative activity against MCF-7, MDA-MB 231 and HT-29 cells. Easpecially IId proved to be the most potent compound. Structure-activity relationship studies indicate that the introduction of acetyl substitution as alternate scaffold of pyrimidin-4-ylamino reduced the activity.

In this study, the novel germatrane compound, 3-(2, 8, 9-trioxa-5-aza-1- germatricyclo [3.3.3.0] undecane-1- yl)-3-(4-hydroxy-3- methoxyphenyl)-propionic acid (1), has been synthesized and its activities against cervical tumor U14 were evaluated in vitro and in vivo. The results have demonstrated that the compound posed significant inhibition on U14 tumor with IC50 values of 48.57 mg/L in cell-based assay and tumor inhibitory rates of 38.50 %, 47.17 % and 64.02 % (from low dose to high dose) in animal experiment.

A set of thirty one substituted 2-phenoxy-N-phenylacetamide derivatives with HIF-1 inhibitory activities was subjected to 2D and 3D Quantitative Structure Activity Relationship (QSAR) studies using various combinations of descriptors. 2D-QSAR was performed using Multiple Linear Regression (MLR), Principal Component Regression (PCR) and Partial Least Squares Regression (PLS) methods. Among these three methods Multiple Linear Regression (MLR) led to the statistically significant best 2D-QSAR Model-I having correlation coefficient r2 = 0.9469 and cross validated squared correlation coefficient q2 = 0.8933 with external predictive ability of pred_r2 = 0.7128 with the descriptors like SssNHE-index, slogp, T_O_N_1 and T_2_Cl_1. 3D-QSAR study was performed using the simulated annealing variable selection procedures k-nearest neighbor molecular field analysis approach. 3D-QSAR shows interesting results in terms of internal and external predictability. Molecular field analysis was applied for the generation of steric, hydrophobic and electrostatic descriptors based on aligned structures which shows good correlative and predictive capabilities in terms of q2 = 0.9672 and pred_r2 = 0.8480. Hence the model proposed in this work provides important structural insight in designing novel derivatives with specific HIF-1 inhibitory activity.

Modern chemotherapy is interested in developing new agents with high efficiency of treatment in low-dose medication strategies, lower side toxicity and stronger specificity to the tumor cells. Vanadocene dichloride (VDC) belongs to the group of the most promising metallocene antitumor agents; however, its mechanism of action and cytotoxicity profile are not fully understood. In this paper we assess cytotoxic effects of VDC in comparison to cisplatin using opposite prototype of cells; human peripheral blood mononuclear (PBMCs) cells and human acute lymphoblastic leukemia cell line (MOLT-4). Our findings showed cytotoxic effect of VDC on leukemia cells, but unfortunately on human peripheral blood mononuclear cells as well. VDC induces apoptosis in leukemia cells; the induction is, however, lower than that of cisplatin, and in contrary to cisplatin, VDC does not induce p53 up-regulation. Cytotoxic effect of VDC on leukemia cells is less pronounced than that of cisplatin and more pronounced in PBMCs than in MOLT-4 cells.

In order to reduce toxicity of methotrexate and improve bioavailability, permeability, and explore other delivery routes, a proline prodrug of methotrexate was synthesized and preformulation stability studies were conducted under accelerated conditions to assess compound liability and possible conversion to the parent drug. Forced degradation studies showed that the prodrug will degrade in the presence of water, acid, and heat (70 °C), generating the parent compound methotrexate. It was also found that this conversion is temperature dependent. In addition, the prodrug is extremely light and oxidative labile. Therefore, future formulation studies should be light protected and stabilized by a suitable antioxidant. It was also found that the prodrug is stable in the HPLC diluent, consisting of water and acetonitrile; stored bench-top and protected from light for up to two weeks.

Hepatitis C virus (HCV) NS5B polymerase is the key replicating protein of the virus and thus an attractive target for drug development. Here we report on the synthesis and biological evaluation of a new series of benzimidazole derivatives as HCV NS5B inhibitors. This yielded compound 6b and 6d bearing 2-(2-benzyloxy)phenyl and 2-(4- methylbenzyloxy)phenyl moieties, respectively, as promising leads. Binding mode of compound 6d in allosteric pocket (AP)-1 of NS5B will form the basis for future structure-activity relationship optimization.

With a view to the rational design of a selected series of 35 imidazopyridazine derivatives, 2D and 3D QSAR models have been developed for the prediction of antimalarial activity. The statistically best 2D QSAR model having r2 = 0.9242 and q2 = 0.8691 with pred_r2 = 0.9206 was developed by SW-MLR and best 3D QSAR model having q2 = 0.8607 with pred_r2 = 0.8332 was developed by k-nearest neighbor molecular field analysis (kNN-MFA). Molecular docking study was also carried out to better understand of the interactions between PfPK7 enzyme target (pdb: 2pnm) and inhibitors in this series. The docking study suggests that these PfPK7 inhibitors interact with Met120, Lys55, Tyr117, Asp123, Leu179, Leu34, Asn35, Ala53, Glu88, Leu101, Tyr119, Ser124, Ser189 and Asp190 amino acid residues of protein PfPK7. Both QSAR and docking studies of such derivatives provide guidance for further lead optimization and designing of more potent PfPK7 inhibitors.

A quantitative structure-activity relationship (QSAR) study has been made on a novel series of pyrrole derivatives acting as lymphocyte-specific kinase (Lck) inhibitors. The Lck inhibition activity of compounds is found to be significantly correlated with their molar volume (MV) and surface tension (ST) and the hydrophobic constant of one of their substituents. Both the molar properties MV and ST of the compounds are found to have the negative effect but the hydrophobic property of R2-substituen is found to have the positive effect. This leads to suggest that the bulky molecules and the those with high surface tension will not be advantageous to the Lck inhibition, rather their R2-substituent with hydrophobic property will be conducive to the activity.

This paper presents results of QSAR (Quantitative Structure Activity Relationship) studies realized with the PRECLAV (Property Evaluation by Class Variables) software. The database contains 66 derivatives of aromatic benzene sulfonamides incorporating 1, 3, 5-triazine moieties, fluorophenyl sulfamates, S-substituted-2-mercaptobenzenesulfonamide and diazenylbenzenesulfonamides with clinically used CA inhibitors. For each molecule over 3600 descriptors were calculated using programs MOPAC, PRECLAV and DRAGON. A heuristic algorithm selects the best multiple linear regression (MLR) equation showed that the correlation between the observed values and the calculated values of activity is very good (N = 66, Se = 0.263, r 2 = 0.884, F = 92.98, r 2 cv = 0.859, Q = 0.794). The virtual molecular fragments that lead to a significant increase of the inhibitor activity of hCA IX are C3H2N5Cl, NH2, C6H4, C3H5N6, COOH, and C3HN6. The virtual fragment – HO, C5H2NO, C3HN6, leads to a significant decrease of the inhibitor activity value. With a view to external validation, the calibration set includes 50 molecules (Se = 0.256, r 2 = 0.885, F = 69.501, r 2 cv = 0.852) and the validation set includes 16 molecules (Se =0.111, r 2 = 0.87, F = 93.984). Identification of molecules in validation set with high estimated value of inhibitory activity of hCA IX is correct enough to have practical value, even if the calibration/ validation set contains aromatic benzene sulfonamides incorporating 1,3,5-triazine moieties and fluor phenyl sulfamates derivatives with very different chemical structures.

Group based Quantitative Structure Activity Relationship (GQSAR) was developed for thirty (4-keto-phenoxy) methyl biphenyl-4-sulfonamides which exhibit aggrecanase-1 enzyme inhibitory activity. This enzyme is involved in osteoarthritis. The data is divided into training and test sets, where the latter is used for validating the model. Substitution in the R1 position plays a major role when compared to substitution in R2 position. The former position is influenced by two descriptors, namely electrotopological and connectivity indices. R2 position is influenced by radius of gyration. The statistical parameters for the training set (r2 = 0.80, r2adj = 0.77, q2 = 0.69, F-ratio = 26.80 and standard error = 0.24) and the predicted r2 (r2 test =0.95) are satisfactory. Docking of the compounds with aggrecanase-1 enzyme showed that there is a strong negative correlation between the binding energy and aggrecanase -1 inhibitory activity. Compounds with the carbonyl substitution interact with the S'1 pocket which is needed for enhanced activity. The two methodologies described here can help in lead optimization.

The synthesis and biological evaluation of hybrid opioids consisting of Naloxone or Naltrexone and a partial opioid peptide are described. These compounds were synthesized in a homogeneous solution as well as in solid phase. A hydrazone linkage was employed to connect the alkaloids to the tetrapeptides. In synthesizing the peptides some non-traditional methods, which provided excellent results, were explored. The solid phase synthesis was achieved by anchoring the Fmoc-Phe to the 2-chlorotrityl resin, followed by stepwise addition of two Fmoc-Gly units. Each addition step preceded by standard piperidine removal of the Fmoc from the prior amino acid (AA) residue. The final AA, Tyr, was added as its Boc derivative. The Boc-tetrapeptide was then separated from the resin with a TFE/AcOH/CH2Cl2 mixture. In the solution synthesis, each peptide elongation step was accomplished by one-pot removal of the Fmoc from the prior AA residue and addition of the next Fmoc-AA. TBAF-thiol was used to cleanly remove the Fmoc, before adding the next Fmoc-AA in the presence of DIPEA and TBTU. All prepared hybrid ligands exhibited high affinities toward all three opioid receptors; moderate preferences for κ and μ receptors over δ receptor were observed. [35S]GTPγS binding assays indicated that these hybrid opioids are δ and μ antagonists but partial κ agonist.

In this paper the authors investigated a synergistic antimycotic effect between four antifungal drugs Amphotericin B, Fluconazole, Tioconazole, and Flucytosine individually combined with Anidulafungin compound. This latter is considered a drug of choice in the treatment of fungal infections; it has good activity both in vitro and in vivo against yeasts and moulds, as Candida and Aspergillus. The goal of this study was to evaluate the in vitro interaction of Anidulafungin in the synergic combinations with previous reported drugs against 12 Candida strains according to CLSI M27-A3 protocol. A synergistic interaction was observed against the most antifungal strains; in particular an increasing of the antimycotic efficacy was obtained from the association between Anidulafungin and Amphotericin B or Fluconazole (Mixture 4:6). In contrast the association Tioconazole/Anidulafungin was less effective on fungal species growth. The antimycotics MIC reduction values were more evident against some strains as C. glabrata, C. krusei, C. tropicalis and C. parapsilosis.

Dopamine (DA) agonists, bearing catechol or phenol rings, are endowed with low oral bioavailability and short effect duration. In this report, the synthesis of novel differently substituted 4-(3-pyridyl)-1,2,3,4-tetrahydroisoquinolines and (1,2,3,4-tetrahydroisoquinolin-4-yl)phenylmethanols as potential non phenolic and non catecholic DA receptor ligands is reported. The new compounds, evaluated by binding tests on cerebral striatal membranes, bound to DA receptors with moderate affinity. Anyhow, they may represent a starting point to develop new DA ligands endowed with better pharmacokinetic and metabolic properties.

Acylhydrazide Schiff bases 1-27 were evaluated for their in vitro DPPH radical and superoxide anion scavenging activity. They showed a varying degree of DPPH radical scavenging activity with IC50 values between 31.25 - 473.59 µM. Compounds 8, 2, and 10 have IC50 values 31.25 ± 1.32, 34.40 ± 0.66, and 37.24 ± 0.4 µM, respectively. Standard npropylgallate showed an IC50 value 30.12 ± 0.27 µM. Acylhydrazides 1-27 exhibited in vitro superoxide anion scavenging activities with IC50 values in the range of 175.6 - 450.89 µM. Results demonstrated that acylhyrazides 8, 2, and 10 have DPPH scavenging activity, comparable to standard n-propyl gallate while acylhyrazides 1-27 were found to be less superoxide anion scavenging active than the standard n-propyl gallate (IC50 = 106.34 ± 1.6 µM).

Multidrug resistance in cancer is a major cause of failure in cancer chemotherapy. In search of new compounds with strong reversal activity and simple molecular structure, we have synthesized a series of compounds in which different substituents were linked to the 2-position of the 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)- tetrahydroisoquinoline system. Compounds were analyzed for their cytotoxicity by MTT in K562 cell line in vitro, all of the derivatives exhibited little cytotoxic activity. In the meantime, these compounds were evaluated by MTT in K562/A02 cell line in vitro, 6e, 6h and 7c exhibited similar or more potent activities than verapamil with the IC50 values at 0.66, 0.65 and 0.96μM, and with the ratio factor of 24.13, 24.50 and 16.59, respectively.

A QSAR study was performed on ninety eight substituted biphenyl analogues of 2-nitroimidazo-[2, 1-b] [1, 3]- oxazines as antitubercular agents to explore the importance of topological, thermodynamic, spatial and physicochemical properties of the molecules towards the antitubercular activity. Genetic function approximation (GFA) was used as the chemometric tool for the study. The study shows that ortho and meta linked attachments of the biphenyl analogs to 2- nitroimidazo-[2, 1-b] [1, 3]-oxazines are detrimental for the antitubercular activity. Hydrophobicity, branching and presence of electronegative atoms enhance the activity. Based on the rm 2 (overall) criterion, which considers both internal validation and external validation, a GFA model with spatial, thermodynamic and topological descriptors appears to be the best model (rm 2 (overall) =0.556).

Folic acid receptors (FR) are usually over expressed in many cancer cells and are considered as potential targeted therapy agent. Generation of five polyamido amine (PAMAM) dendrimer folic acid conjugate was synthesised and radiolabelled with 188Re, furthermore the in vitro/in vivo stability was evaluated accordingly. The labelling yield of the conjugate G5-FA-DTPA-188Re was 67.1 % and its radiochemical purity exceeded 95 %. The conjugate also showed high in vitro stability and potential value for further structure modifications and evaluations.

The development of new antimicrobial agents for the treatment of infectious diseases remains challenging due to the increasing impact of antibiotic resistance. Since salicylanilides and esters of pyrazine-2-carboxylic acid have been described as potential antimicrobials, we have designed and synthesized a series of 2-(phenylcarbamoyl)phenyl pyrazine-2-carboxylates. These were evaluated in vitro for the activity against fungi and Gram-positive and Gram-negative bacteria. All derivatives showed significant antibacterial activity against Gram-positive strains (MIC ≥ 0.98 µmol/L) including methicillin-resistant Staphylococcus aureus. The most active molecule was 5-chloro-2-(3-chlorophenylcarbamoyl)phenyl pyrazine-2-carboxylate. With one exception these esters were at least partly active against fungi tested strains, in particular against mould strains (MIC ≥ 1.95 µmol/L). The most active antifungal agent overall proved to be 2-(4-bromophenylcarbamoyl)-4-chlorophenyl pyrazine-2-carboxylate.

Fifteen derivatives of 8-oxocoptisine were prepared based on that 8-oxocoptisine showed potent reversing effect against human cancer cells charactering multidrug resistance (MDR). The derivatives were evaluated for their growth inhibition and effects on reversing P-gp-mediated MDR against MCF-7/AMD cells. 12, 13-dinitro-8-oxocoptisine (6c), the most potential candidate with weak growth inhibition, significantly increased the sensitivity of adriamycin (ADM) against MCF-7/ADM cells by 213-fold at 10μM that was comparable to the reference compound verapamil. The preliminary structure-activity relationships (SARs) of these derivatives were discussed on the basis of the in vitro MDR reversal activities.

The role of vasopressin (AVP) in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is elevated in heart failure and some forms of hypertension. Also, AVP has vasoconstrictor, mitogenic, hyperplasic and renal fluid retaining properties which, by analogy with angiotensin II, may have deleterious effects when present in chronic excess. Furthermore, cholesterol blood levels are also associated with hypertension, although the underlying mechanism is not known. Here we analyze the relationship between blood total cholesterol levels and serum vasopressin- degrading cystyl-aminopeptidase activity (AVP-DA) in healthy humans, and the differences between men and women. Linear correlation coefficients were calculated to test relationships between AVP-DA and blood total cholesterol levels. Sex differences were observed for AVP-DA, being this activity higher in men than in women. According to the linear model of the regression analysis, AVP-DA showed a significant negative correlation with blood total cholesterol levels in men, whereas no correlation was observed in women. Several studies in humans demonstrate the existence of greater plasma AVP concentrations in normal men compared to normal women, which could explain the genderdifferences observed in the present work in relation with AVP-DA. However, AVP-DA is related to blood cholesterol levels only in men, although in our hands, women showed higher blood cholesterol levels than men. This could indicate that the risk of high cholesterol-related hypertension is more probable in men than in women. Although AVP-DA misregulation could be involved in the pathogenesis of hypertension, its relation with cholesterol levels appears only in men, but not in women.

Poor bioavailability of topically instilled drug is the major concern in the field of ocular drug delivery. Efflux transporters, static and dynamic ocular barriers often possess rate limiting factors for ocular drug therapy. Different formulation strategies like suspension, ointment, gels, nanoparticles, implants, dendrimers and liposomes have been employed in order to improve drug permeation and retention by evading rate limiting factors at the site of absorption. Chemical modification such as prodrug targeting various nutrient transporters (amino acids, peptide and vitamin) has evolved a great deal of interest to improve ocular drug delivery. In this review, we have discussed various prodrug strategies which have been widely applied for enhancing therapeutic efficacy of ophthalmic drugs. The purpose of this review is to provide an update on the utilization of prodrug concept in ocular drug delivery. In addition, this review will highlight ongoing academic and industrial research and development in terms of ocular prodrug design and delivery.