ANTIBACTERIAL PREDRUGS-FROM 1899 TILL 2015

The classical approach for delivery of drugs into the central nervous system (CNS) is associated with adverse effects and it has many limitations. Therefore, extensive efforts have been done in searching and developing novel methods for achieving such delivery. This minireview discusses the design and synthesis of selected targeting prodrugs for the treatment of conditions related to impairment in the CNS such as Parkinson‘s and Alzheimer‘s diseases. Such approaches include targeting prodrugs which are designed to interact with unique cellular conditions at the target site, especially the availability of certain enzymes and transporters at these sites. In addition, part of this mini-review is devoted to prodrugs design based on enzyme models that have been invoked to understand how enzymes catalyzebiotransformation. In this approach, the prodrugs design isdone using quantum molecular orbital and molecular mechanics methods. The equations obtained from correlations of experimental and calculated rate values for some intramolecular processes are used to predict parameters for other intramolecular processes that can be utilized as prodrugs linkers. In this approach, there is no need for enzymes to catalyze the conversion of the prodrug to its active parent drug and the conversion rate of the prodrug is dependent only on those factors playing dominant role in the rate-limiting step of the process

Diclofenac Codrugs and Prodrugs-Three Decades of Design

Prodrugs or predrugs are inactive molecules which become active after in vivo conversion to release the active parent drug. The prodrug’s cleavage can be catalyzed by metabolic enzymes or can occur by chemical means without the involvement of enzymes. Prodrugs are designed to improve undesirable physicochemical and pharmacokinetic properties of their parent drugs. Non-steroidal anti-inflammatory (NSAIDs) drugs are among the most commonly used drugs for treatment of pain, inflammation and fever. Despite their frequent use, these agents suffer from gastrointestinal side effects that limit their use for those patients with gastrointestinal conditions. This mini review discusses the design, synthesis and pharmacological effects of prodrugs and codrugs of the non-steroidal anti-inflammatory (NSAIDs) Diclofenac sodium or potassium. It argues that the prodrug approach has the potential to eliminate Diclofenac associated gastrointestinal complications, increases its bioavailability and masks its bitter taste

Mefenamic acid Prodrugs and Codrugs- Two Decades of Development

prodrugs are bioreversible derivatives of drug molecules that undergo intermolecular or intramolecular reactions by enzymatic or chemical biotransformation in the human body to give the corresponding active parent drugs and a non-toxic promoiety. Prodrugs have been extensively and successfully used as a chemical tool for modification of the physicochemical, pharmacokinetic as well as pharmacodynamic characteristics of commonly used drugs and new drugs.This mini review focuses on the design, synthesis and pharmacological effects of several prodrugs and codrugs of the non-steroidal anti-inflammatory (NSAIDs), mefenamic acid. Exploitation of the prodrug approach has the potential to achieve a reduction of mefenamic acid GI (gastrointestinal) intolerance, enhance its bioavailability, mask its unpleasant sensation and prolong its duration of action. In addition, utilizing the prodrug concept migh enhance the bioavailability of the counter partner drug of mefenamic acid codrug by increasing its lipophilicity

Antibacterial Predrugs-from 1899 till 2015

The predrug (prodrug) term involves chemically modified inert compound which upon an administration releases the active parent drug to elicit its pharmacological response within the body. For many years, the predrug strategy has been extensively developed to solve many unwanted drug properties. This approach has several advantages over conventional drug administration and it has the potential to be quite effective method for the treatment of diseases in the future. In this mini-review we describe a number of antibacterial agents‘ predrugs, and the ways by which predrug strategy was exploited to overcome many pharmaceutical and pharmacokinetic problems that the parent active antibacterial drugs suffer from such as, low bioavailability by increasing or decreasing lipophilicity, site selectivity for higher absorption and less toxicity, short duration of action to increase patient compliance, rapid metabolism to increase oral bioavailability and masking bitter sensation which is crucial for geriatric and pediatric patient compliance

Mefenamic acid prodrugs and codrugs - two decades of development

prodrugs are bioreversible derivatives of drug molecules that undergo intermolecular or intramolecular reactions by enzymatic or chemical biotransformation in the human body to give the corresponding active parent drugs and a non-toxic promoiety. Prodrugs have been extensively and successfully used as a chemical tool for modification of the physicochemical, pharmacokinetic as well as pharmacodynamic characteristics of commonly used drugs and new drugs.This mini review focuses on the design, synthesis and pharmacological effects of several prodrugs and codrugs of the non-steroidal anti-inflammatory (NSAIDs), mefenamic acid. Exploitation of the prodrug approach has the potential to achieve a reduction of mefenamic acid GI (gastrointestinal) intolerance, enhance its bioavailability, mask its unpleasant sensation and prolong its duration of action. In addition, utilizing the prodrug concept migh enhance the bioavailability of the counter partner drug of mefenamic acid codrug by increasing its lipophilicity

Anti-cancer Prodrugs-Three Decades of Design

The conventional old treatment method for cancer therapy is associated with severe side effects along with several limitations. Therefore, searching and developing new methods for cancer became crucial. This mini review was devoted on the design and synthesis of prodrugs for cancer treatment. The methods discussed include targeted prodrugs which are depending on the presence of unique cellular conditions at the desired target, especially the availability of certain enzymes and transporters at these target sites, antibody directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) which is considered one of the important strategies for the treatment of cancer and prodrugs based on enzyme models that have been advocated to understand enzyme catalysis. In this approach, a design of prodrugs is accomplished using computational calculations based on molecular orbital and molecular mechanics methods. Correlations between experimental and calculated rate values for some intramolecular processes provided a tool to predict thermodynamic and kinetic parameters for intramolecular processes that can be utilized as prodrugs linkers. This approach does not require any enzyme to catalyze the prodrug interconversion. The interconversion rate is solely dependent on the factors govern the limiting step of the intramolecular process

Antibacterial Activity of Novel Prodrugs of Amoxicillin and Cephalexin

Two novel prodrugs of amoxicillin and cephalexin (amoxicillin ProD 1 and cephalexin ProD 1, respectively) were designed and synthesized to improve the stability and bitter sensation of their parent drugs. The in vitro susceptibility for both prodrugs was determined against Escherichia coli, staphylococcus epidermidis, staphylococcus aureus, Klebsiella pneumonia, streptococcus group A and streptococcus group B, and was compared to that of their active parent drugs.The antibacterial screening demonstrates that amoxicillin ProD 1 and cephalexin ProD 1 were found to be active and are considered among a small number of prodrugs that have therapeutic activity themselves before undergoing interconversion via enzymatic or chemical reaction to their corresponding active parent drugs. Both prodrugs exhibit their antibacterial activity against different types of bacterial strains due to the presence of β- lactam ring in their structures. In addition, it is expected that these novel prodrugs will be much more stable in aqueous media than their corresponding active parent drugs due to the fact that the chemically sensitive amine group contained in the active parent drug structures is replaced with an amide, more chemically stable group, in the corresponding prodrugs

Synthesis and Characterization of Designed Tranexamic Acid and Paracetamol Prodrugs

Prodrug is a chemical devise in which the drug is covalently linked to a chemical moiety; this linked moiety will temporarily affect the physicochemical properties of the drug for increasing their usefulness or decreasing their toxicity. The prodrug should be converted to its active form by metabolic or/and chemical processes, conversion process involves metabolism by enzymes distributed throughout the body. These enzymes might either decrease the drug’s bioavailability, or a genetic polymorphisms might lead to variability in prodrug activation and thus affect the efficacy and safety of designed prodrug. In the past few decades computational chemistry methods have been utilized in calculating physicochemical and molecular properties of compounds. This tool can be used to design prodrugs that chemically (intramolecular processes) interconvert to their parent drugs without any involvement of enzyme catalysis. The release of the active drug is solely dependent on the rate limiting step of the intramolecular process. Based on DFT calculations four different tranexamic acid prodrugs and three different bitter less paracetamol prodrugs were designed, synthesized and characterized using FT-IR, 1H-NMR LCMS and their in vitro intra-conversion to their parent drugs revealed that the t1/2 was largely affected by the pH of the medium. For tranexamic acid ProD 1 the experimental t1/2 values in 1N HCl, buffer pH 2 and buffer pH 5 were 54 minutes, 23.9 hours and 270 hours, respectively. Tranexamic acid ProD 2 was readily converted in 1 N HCl and pH 2 while it was entirely stable at pH 5 and pH 7.4. On the other hand, tranexamic acid ProD 3 and Prod 4 were stable in all media studied. The experimental t1/2 values for paracetamol ProD 2 in pH 3 and pH 7.4 were 3 hours and 18 minutes respectively and for paracetamol ProD 3 it was 27 hours in pH 3 and 12 hours in pH 7.4. In vitro binding for paracetamol ProD 2 to bitter taste receptors revealed that this prodrug lacks any binding affinity and it was found not to have any bitter sensation. This suggests, that paracetamol ProD 2 can replace its parent drug, paracetamol, for the use asbitterless antipyretic drug for geriatrics and pediatrics

Overview on the Recent Drugs Delivery Approaches

This review provides the reader a concise overview of the different biological barriers that hinder the delivery of therapeutic agents through membranes, such as intestinal mucosa, Brain Blood Barrier (BBB), and mediators of transport such as efflux transporters and etc., and the approaches for overcoming such barriers. The approaches discussed in this review include: utilizing natural occurring transporters to deliver drugs specifically to their targets, nucleoside analogues delivery, CYPactivated prodrugs that target drugs to the liver, modification of passive diffusion by efflux pumps, intestinal transporters such as PEPT1 and GLUT1, Carrier Mediated Transport (CMT) systems for transporting nutrients, vitamins or hormones into the central nervous system, tissue selective drug delivery, administration of an exogenous enzyme to reach the tumor site which is followed by systemic administration of non-toxic prodrugs (ADEPT, GDEPT and VDEPT), enzymes involve in the bioconversion of ester-based prodrugs for activation (hydrolysis) of prodrugs to their active forms, brain targeted Chemical Delivery Systems (CDS), amino acid prodrugs to improve oral bioavailability, sustained drug delivery and intravenous drug delivery. In addition, Receptor-Mediated Transcytosis (RMT) for efficacious delivery of Nano particles through the intestinal mucosa and BBB, and the prodrug chemical approach based on intra molecularity to deliver anti-cancer drugs is discussed