Prodrugs for Masking Bitter Taste of Antibacterial Drugs - A Computational Approach

DFT calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. Further, it was established that when the amine leaving group was a secondary amine, acyclovir or cefuroxime moiety the tetrahedral intermediate formation was the rate-limiting step such as in the cases of acyclovir ProD 1- ProD 4 and cefuroxime ProD 1- ProD 4. In addition, the linear correlation between the calculated and experimental rates provided a credible basis for designing prodrugs for masking bitter taste of the corresponding parental drugs which have the potential to release the parent drug in a sustained release fashion. For example, based on the DFT calculated rates the predicted t1/2 (a time needed for 50 % of the reactant to be hydrolyzed to products) for cefuroxime prodrugs, cefuroxime ProD 1- ProD 4, were 12 min, 18 min, 200 min and 123 min, respectively

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these Editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs

A Novel Mathematical Equation For Calculating The Number of ATP Molecules Generated From Sugars In Cells

Adenosine triphosphate (ATP) is critical for all life from the simplest to the most complex. All organisms from the microscopic to humans utilize ATP as the source for their primary energy currency. This manuscript describes a novel method to calculate the number of ATP molecules generated from the consumption of any sugar (having 3-7 carbons). This calculation method based on the oxidation states of the sugar’s carbons. The time needed to calculate the number of ATP molecules by this method is less than 2 minutes whereas that required by the current (regular) method is many hours and even days in some cases. In addition, the current method requires drawing all biochemical processes that the sugar undergoes upon its cellular respiration (oxidation) while our method described herein does not

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

The prodrug approach in the era of drug design

Prodrugs are inactive precursors of an active drug designed to be bioconverted (activated) post administration with the main aim of improving the pharmacokinetic properties of the parent drug. Prodrugs have been successful for a longtime. Sulfasalazine, one of the earliest prodrugs, reaches the colon and is metabolized by bacteria into two active metabolites: sulfapyridine and 5-aminosalicylic acid (5-ASA). Sulfasalazine was approved for use in the USA in 1950 and still is considered first-line treatment in autoimmune conditions such as Crohn’s disease and ulcerative colitis [1]. It has been demonstrated that the prodrug approach has reached vast success in the past few years. It is estimated that around 10% of all marketed drugs are prodrugs, 20% of small molecular weight drugs approved between 2000 and 2008 were prodrugs, and between 2008 and 2017 the share of prodrugs in the drug market was 12% [2]. Various strategies are employed in the prodrug approach. The most common of which is making a prodrug susceptible to abundant enzymes by functionalization with a group that can be cleaved to produce the active form of the drug. The prodrug approach to drug optimization offers chemical stability such as an inactive oral prodrug can be stable in the gastrointestinal tract and only be bioconverted by CYP450 in the liver, plasma, or GIT mucosal esterase, or other enzymes. Examples of this include phosphate groups which are susceptible to alkaline phosphatase, ester groups which are susceptible to esterases, and carbamates or amidine groups which are susceptible to amidases. Newer strategies include pegylation, which is used to increase cellular uptake, and dimer prodrugs, which are cleaved to two active moieties. Also, prodrugs can be used as precursors in biological conversion pathways, as is the case with L-dopa, a prodrug of dopamine. L-dopa crosses the blood-brain barrier through L-type amino acid transporter-1 and is metabolized by aromatic amino acid decarboxylase to active dopamine in the CNS. Targeted prodrugs have also been explored in oncology in order to minimize side effects and improve the tolerability of chemotherapy [3]. Prodrugs are also used to increase the duration of action of medicines, acting as chemical sustained release forms. Lisdexamfetamine dimesylate is an inactive prodrug of amphetamine used mainly in the treatment of attention deficit hyperactivity disorder (ADHD). The prodrug is hydrolyzed by red blood cells to L-lysine and active d-amphetamine. The duration of action of lisdexamfetamine is 12 h [4] compared to that of instant release amphetamine, which is 3-6 h. In cardiovascular medicine, prodrugs have been successful. Older prodrugs such as angiotensin-converting enzyme inhibitors (ACEi) are considered cornerstones in the management of hypertension. ACE inhibitors are dicarboxyl ester prodrugs converted to their active -rilat form by liver esterase (such as enalapril and enalaprilat). The exceptions for this are lisinopril and captopril which are not prodrugs, and fosinopril, which is a phosphonic acid prodrug hydrolyzed by liver and GIT mucosa esterases. Newer prodrugs, such as dabigatran etexilate and prasugrel (Table 1), are anticoagulants indicated for the treatment and prevention of blood clotting. Prodrugs of nucleoside analogs are used to improve pharmacokinetic properties such as intestinal permeability and oral absorption [15]. For instance, valacyclovir and valganciclovir are valine ester prodrugs of acyclovir and ganciclovir, respectively, target intestinal oligopeptide transporter aiming to improve the oral absorption of the parent drug.This paper was not funded

Computationally Designed Enzyme Models to Replace Natural Enzymes in Prodrug Approaches

The striking efficiency of enzyme catalysis has inspired many organic chemists to explore enzyme mechanisms by studying certain intra molecular processes such as enzyme models which proceed faster than their intermolecular counterparts. This research brings about the important question of whether enzyme models will replace natural enzymes in the conversion of prodrugs to their parental drugs. Enzymes are mandatory for the inter conversion of many prodrugs to their parental drugs. Among the most important enzymes in the bioconversion of prodrugs are amides (ex. trypsin, chymotrypsin, elastase, carboxypeptidase, and aminopeptidase) and ester-based prodrugs (ex. paraoxonase, carboxylesterase, acetylcholinesterase and cholinesterase). Most of these enzymes are hydrolytic enzymes, however, non-hydrolytic enzymes, including all cytochrome P450 enzymes, are also capable of catalyzing the bioconversion of ester and amide-based prodrugs [1].The author would like to acknowledge funding by the German Research Foundation (DFG, ME 1024/8-1)

Prodrugs from Serendipity to Design by Computational Chemistry Methods

Imagination is more important than knowledge when knowledge is limited and can not solve important questions. Inventiveness in the drug design has been clumsiness in quality and quantity. This may be due to the ineptness and incapability of medicinal chemists to comprehend biochemistry and biology issues. On the other hand, biochemists, biologists, and pharmaceutical chemists do not possess the expertise to make complex organic entities. Hence, a team comprising of all expertise is a must to invoke a novel drug

Newly Developed Prodrugs and Prodrugs in Development; an Insight of the Recent Years

Background: The design and development of prodrugs is the most common and e ective strategy to overcome pharmacokinetic and pharmacodynamic drawbacks of active drugs. A respected number of prodrugs have been reached the drugs market throughout history and the recent years have witnessed a significant increase in the use of prodrugs as a replacement of their parent drugs for an e cient treatment of various ailment. Methods: A Scan conducted to find recent approved prodrugs and prodrugs in development. Results: Selected prodrugs were reported and categorized in accordance to their target systems. Conclusions: the prodrug approach has shown many successes and still remains a viable and e ective approach to deliver new active agents. This conclusion is supported by the recent approved prodrugs and the scan of clinical trials conducted between 2013–2018.Funding: This research received no external funding. Acknowledgments: The authors would like to thank Al-Quds University-Scientific Research O ce for covering the publication fees for this review article

Computer-Assisted Design for Paracetamol Masking Bitter Taste Prodrugs

It is believed that the bitter taste of paracetamol, a pain killer drug, is due to its hydroxyl group. Hence, it is expected that blocking the hydroxy group with a suitable linker could inhibit the interaction of paracetamol with its bitter taste receptor/s and hence masking its bitterness. Using DFT theoretical calculations we calculated proton transfers in ten different Kirby’s enzyme models, 1–10. The calculation results revealed that the reaction rate is linearly correlated with the distance between the two reactive centers (rGM) and the angle of the hydrogen bonding (α) formed along the reaction pathway. Based on these results three novel tasteless paracetamol prodrugs were designed and the thermodynamic and kinetic parameters for their proton transfers were calculated. Based on the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for processes 1–10 we have calculated the t1/2 values for the conversion of the three prodrugs to the parental drug, paracetamol. The calculated t1/2 values for ProD 1–3 were found to be 21.3 hours, 4.7 hours and 8 minutes, respectively. Thus, the rate by which the paracetamol prodrug undergoes cleavage to release paracetamol can be determined according to the nature of the linker of the prodrug (Kirby’s enzyme model 1–10). Further, blocking the phenolic hydroxyl group by a linker moiety is believed to hinder the paracetamol bitterness.The Karaman Co. is thanked for support of our computational facilities. Special thanks are also given to Angi Karaman, Donia Karaman, Rowan Karaman and Nardene Karaman for technical assistance