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The aim of this paper was to emphasize the importance of prodrug design to therapy, by examining examples available on the Brazilian pharmaceutical market. The principles of prodrug design are briefly discussed herein. Examples of prodrugs from many important therapeutic classes are shown and their advantages relative to the drugs they are derived...
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Cardiotoxicity has historically been a major cause of drug removal from the pharmaceutical market. Several chemotherapeutic compounds have been noted for their propensities to induce dangerous cardiac-specific side effects such as arrhythmias or cardiomyocyte apoptosis. However, improved preclinical screening methodologies have enabled cardiotoxic...
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... The chemical reaction involves the acetylation of salicylic acid, resulting in the formation of aspirin and acetic acid ( Figure 23). The reaction is as follows: The specific ester bond in aspirin is between the oxygen atom of the hydroxyl group in salicylic acid and the carbon atom of the carbonyl group in acetic anhydride [73]. This ester linkage is what gives aspirin its chemical structure. ...
... In the present work, both structural and electronic properties, harmonic vibrational The specific ester bond in aspirin is between the oxygen atom of the hydroxyl group in salicylic acid and the carbon atom of the carbonyl group in acetic anhydride [73]. This ester linkage is what gives aspirin its chemical structure. ...
Psoriasis is a chronic autoimmune skin disorder characterized by the rapid overproduction of skin cells, resulting in the formation of red, inflamed, and scaly patches or plaques on the skin. Dithranol, also known as anthralin, is a very effective topical medication used in the treatment of psoriasis, with several shortcomings like photo-instability; staining skin, clothing, and bedding; and causing skin irritation. Antiproliferative dithranol is frequently used in combination therapy with keratolytic salicylic acid. We have therefore proposed a novel topical antipsoriatic prodrug comprising dithranol and salicylic acid joined together with an ester bond, specifically 8-hydroxy-9-oxo-9,10-dihydroanthracen-1-yl-2-hydroxybenzoate. An ester bond is cleavable by endogenous esterase hydrolyzing this bond and releasing dithranol and salicylic acid in a 1:1 stoichiometric ratio. We performed an exhaustive theoretical analysis of this molecule using the reliable computational methods of quantum chemistry and ADME in silico studies to investigate its biological and pharmacokinetic activities. We found its molecular structure, vibrational spectra, molecular orbitals, MEP (molecular electric potential), UV-VIS spectra, and TDOS (total density of states), and we performed an RDG (reduced density gradient) analysis. The obtained results may be useful for the understanding of its properties, which may assist in the synthesis and further experimental study of this possible antipsoriatic dual-action prodrug with reduced adverse effects and enhanced therapeutic efficacy.
... The word Prodrug was introduced by Adrien Albert in 1951 and the concept was identified by Harper in 1959 [1,2] . According to Harper, the word latentiated indicating to drugs that need bioactivation [3] . This description is the most suitable even at present moment and is consistent with the International Union of Pure and Applied Chemistry (IUPAC) definition which states that a prodrug is a biologically inactive molecule that is altered into an energetic active drug by an enzymatic or chemical process [4] . ...
... This work has explored a different approach than co-crystals to modulate the RAA and NP systems using a single molecular entity that chemically combines the pharmacophores of AT1 antagonists and NEP inhibitors into reciprocal prodrugs (also named codrugs). Codrugs are defined as two active molecules that are combined into a single molecule through a cleavable linker, which is enzymatically hydrolyzed in vivo, releasing the active molecules (PariseFilho et al., 2010). Codrugs are useful when a combination therapy is desirable but one of the active molecules or both show poor oral exposure as individual molecular entities. ...
The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists Losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver S9 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them prodrugs, but bearing only the AT1 pharmacophore.
... Carbamates are used as prodrugs of alcohols and phenols to achieve systemic hydrolytic stability and protection from first-pass metabolism (23). Carbamates of N-monosubstituted and N, N-disubstituted alcohols are chemically stable against hydrolysis (21), as are the carbamates of N, N-disubstituted phenols but not as much those of N-monosubstituted phenols (21,24). Examples of carbamate prodrugs whose active substance is alcohol or phenol are irinotecan and bambuterol (Figure 1). ...
... Bambuterol belongs to long-acting drugs due to catecholic hydroxyl groups in its structure that are quite resistant to hydrolysis and first-pass metabolism. In the lung tissue, bambuterol is hydrolysed to terbutaline by BChE (Figure 12), and in the liver, it is metabolised to terbutaline under the influence of cytochrome P-450-dependent oxidases (24,107,109). Terbutaline is an adrenergic agonist that predominantly stimulates ß-2 receptors to relax the smooth muscle of the bronchus and dilate the airways (107)(108)(109). ...
Due to their very good chemical and proteolytic stability, ability to penetrate cell membranes, and resemblance to a peptide bond, carbamate derivatives have received much attention in recent years and got an important role in modern drug discovery and medicinal chemistry. Today, carbamates make structural and/or functional part of many drugs and prodrugs approved and marketed for the treatment of various diseases such as cancer, epilepsy, hepatitis C, HIV infection, and Alzheimer’s disease. In drugs they can play a role in drug-target interaction or improve the biological activity of parent molecules. In prodrugs they are mainly used to delay first-pass metabolism and enhance the bioavailability and effectiveness of compounds. This brief review takes a look at the properties and use of carbamates in various fields of medicine and provides quick insights into the mechanisms of action for some of them.
... PBPs are responsible for the synthesis of peptidoglycans (PGs) that form the rigid cell walls of bacteria such as E. coli [74]. The side chain of the β-lactam structure controls the range of antimicrobial activity as well as the compound's pharmacokinetic properties [86]. Ampicillin is suitable for this study because its mode of action targets bacterial cell wall properties which can be easily probed with AFM [77,80]. ...
Persister bacterial cells are great at surviving antibiotics. The phenotypic means by which they do that are underexplored. As such, atomic force microscope (AFM) was used to quantify the contributions of the surface properties of the outer membrane of multidrug resistance (MDR)-Escherichia coli Strains (A5 and A9) in the presence of ampicillin at minimum inhibitory concentration (MIC) (resistant cells) and at 20× MIC (persistent cells). The properties quantified were morphology, root mean square (RMS) roughness, adhesion, elasticity, and bacterial surface biopolymers’ thickness and grafting density. Compared to untreated cells, persister cells of E. coli A5 increased their RMS, adhesion, apparent grafting density, and elasticity by 1.2, 3.4, 2.0, and 3.3 folds, respectively, and decreased their surface area and brush thickness by 1.3 and 1.2 folds, respectively. Similarly, compared to untreated cells, persister cells of E. coli A9 increased their RMS, adhesion and elasticity by 1.6, 4.4, and 4.5 folds, respectively; decreased their surface area and brush thickness by 1.4 and 1.6 folds, respectively; and did not change their grafting densities. Our results indicate that resistant and persistent E. coli A5 cells battled ampicillin by decreasing their size and going through dormancy. The resistant E. coli A9 cells resisted ampicillin through elongation, increased surface area, and adhesion. In contrast, the persistent E. coli A9 cells resisted ampicillin through increased roughness, increased surface biopolymers’ grafting densities, increased cellular elasticities, and decreased surface areas. Mechanistic insights into how the resistant and persistent E. coli cells respond to ampicillin’s treatment are instrumental to guide design efforts exploring the development of new antibiotics or renovating the existing antibiotics that may kill persistent bacteria by combining more than one mechanism of action.
... Ampicillin was chosen as a model β-lactam antibiotic to use in this study. In this group of antibiotics, the side chain in the structure regulates the antimicrobial spectrum and pharmacokinetic properties of the compound (Filho et al., 2010). The β-lactam ring in the ampicillin core structure is responsible for the antibacterial function via the inhibition of the PBP [ Fig. S2D]. ...
The roles of the thicknesses and grafting densities of the surface biopolymers of four multi-drug resistant (MDR) Escherichia coli bacterial strains that varied in their biofilm formation in controlling cellular elasticities after exposure to ampicillin were investigated using atomic force microscopy. Exposure to ampicillin was carried out at minimum inhibitory concentrations for different duration times. Our results indicated that the four strains resisted ampicillin through variable mechanisms. Strain A5 did not change its cellular properties upon exposure to ampicillin and as such resisted ampicillin through dormancy. Strain H5 increased its biopolymer brush thickness, adhesion and biofilm formation and kept its roughness, surface area and cell elasticity unchanged upon exposure to ampicillin. As such, this strain likely limits the diffusion of ampicillin by forming strong biofilms. At three hours' exposure to ampicillin, strains D4 and A9 increased their roughness, surface areas, biofilm formation, and brush thicknesses and decreased their elasticities. Therefore, at short exposure times to ampicillin, these strains resisted ampicillin through forming strong biofilms that impede ampicillin diffusion. At eight hours' exposure to ampicillin, strains D4 and A9 collapsed their biopolymers, increased their apparent grafting densities and increased their cellular elasticities. Therefore, at long exposure times to ampicillin, cells utilized their higher rigidity to reduce the diffusion of ampicillin into the cells. The findings of this study clearly point to the potential of using the nanoscale characterization of MDR bacterial properties as a means to monitor cell modifications that enhance "phenotypic antibiotic resistance".
... After absorption, enzymatic hydrolysis occur , followed by a chemical rearrangement due to the electronic characteristics of the intermediary formed, thus releasing their active parent drugs. [34] O Erythromycin is a macrolide antibiotic, consists of 14-atom lactone to which two sugars are bonded. One of these sugars features an amino group which gives the drug the characteristic of a weak base that enables the formation of salts with organic acids. ...
... The active parent drug, erythromycin, is released into the bloodstream or muscle tissue after the action of esterases on its ester predrugs ( Figure 15). [34] Rafik et al. The Desire to develop a ‗dual-action cephalosporin' antibiotics that intended to expel potent antibacterial agents when acted upon by βL producing bacterial strains set the phase for designing cephalosporin-containing anticancer predrugs. ...
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.
KEYWORDS: Predrugs, Prodrugs, Antibacterials predrugs, Antibacterial agents, Predrug chemical approach, Intramolecular process, Bitter sensation.
... Regarding prodrug design strategy, or latentiation method, the main purpose is to modify physicochemical properties of drugs to reduce undesirable pharmacokinetic features, but maintaining drug's intrinsic activity. Thus, the drugs' physicochemical properties can be adjusted through a proper choice of carrier groups in order to increase oral absorption, for example (11,12). ...
... The set of prodrugs (PRO) and parent drugs were selected from reference Parise-Filho et al. (12). Regarding the commercially available prodrugs, those classified as classical prodrugs, which were designed in order to improve bioavailability, were randomly selected. ...
Purpose - Prodrug design is a strategy that can be used to adjust physicochemical properties of drugs in order to overcome pharmacokinetic problems, such as poor oral bioavailability. However, Lipinski´s and Veber´s rules predict whether compounds will have absorption problems even before the design of prodrugs. In this context, our goal was to evaluate the molecular properties which most influenced the absorption process of prodrugs compared to its precursor through exploratory data analysis approach.
A variety of prodrugs and respective precursors were randomly selected and classified by its percentage of human intestinal absorption. Subsequently, different molecular properties were calculated and hierarchical cluster analysis (HCA) and principal components analysis (PCA) were carried out.
According to the findings, antiviral, anti-hypertensive, and antibiotic prodrugs exhibited higher absorption levels than their respective precursors. Also, some relevant descriptors (molecular weight, MW, routable bonds, rot_bonds, hydrogen bond acceptors, HBA_count and polar surface area, PSA), which are included in Lipinski´s and Veber´s rules, influenced the separation process between prodrugs and drugs. Furthermore, other molecular properties, such as polarizability (α) and molar refractivity (MR), were pointed out.
Lipinski´s and Veber´s rules proved to be important to design an orally administered drug but other descriptors should be considered by medicinal chemists in the prodrug designing process.
... Entre os métodos de planejamento de fármacos merece destaque a latenciação. Esta estratégia de modificação molecular consiste na alteração estrutural de uma molécula pré-existente, denominada protótipo ou precursor, a fim de originar um derivado temporariamente inativo (pró-fármaco), que apresente características farmacêuticas e/ou farmacocinéticas aprimoradas em relação à molécula de partida (Parise-Filho et al., 2010;Chung & Ferreira, 1999;Korolkovas & Burckhalter, 1988). ...
... Figura 1: Representação esquemática do conceito de pró-fármaco (F=fármaco, T=transportador, F-T = pró-fármaco). Fonte: Parise-Filho et al., 2010. Nesse contexto, o planejamento/desenvolvimento de pró-fármacos tem como principal objetivo superar diversos obstáculos ou barreiras biológicas que possam limitar o uso de um fármaco, tais como baixa solubilidade (hidro ou lipossolubilidade), sabor ou odor inadequado, irritação ou dor no local de aplicação, permeabilidade insuficiente pela barreira hemato-encefálica, extenso metabolismo présistêmico e baixa biodisponibilidade oral (Pereira, 2007;Chung & Ferreira, 1999). ...
... Nesse contexto, o planejamento/desenvolvimento de pró-fármacos tem como principal objetivo superar diversos obstáculos ou barreiras biológicas que possam limitar o uso de um fármaco, tais como baixa solubilidade (hidro ou lipossolubilidade), sabor ou odor inadequado, irritação ou dor no local de aplicação, permeabilidade insuficiente pela barreira hemato-encefálica, extenso metabolismo présistêmico e baixa biodisponibilidade oral (Pereira, 2007;Chung & Ferreira, 1999). Assim, a latenciação permite, entre outras vantagens, a reintrodução de substâncias anteriormente descartadas por suas propriedades indesejáveis e ainda o aprimoramento de novos fármacos, antes mesmo que sejam lançados na terapêutica (Parise-Filho et al., 2010;Chung et al., 2008;Rautio et al., 2008;Waller & George, 1989;Stella et al., 1985). ...
Prodrug design is an important tool in the drug discovery process, since many biological barriers that limit the use of a drug may be overcome by a prodrug precursor. This strategy allows the improvement of new drugs before they are marketed and also enables the reintroduction of substances previously discarded for their undesirable properties. Although clinical advantages of prodrug design are well-established, there are no studies demonstrating the economic benefits of using prodrugs rather than the intended drugs. The aim of this study was to elaborate a technical report on the relative cost of treatments carried out with prodrugs or with the related drugs. This study was intended to demonstrate the real importance of prodrug design as a guiding tool for drug development and the financial viability of the use of prodrugs. It was found that six of the analyzed prodrugs were financially advantageous compared to the actual drugs and that, even for the prodrugs that had a higher cost, the clinical advantage justified their therapeutic use.
... Entre os métodos de planejamento de fármacos merece destaque a latenciação. Esta estratégia de modificação molecular consiste na alteração estrutural de uma molécula pré-existente, denominada protótipo ou precursor, a fim de originar um derivado temporariamente inativo (pró-fármaco), que apresente características farmacêuticas e/ou farmacocinéticas aprimoradas em relação à molécula de partida (Parise-Filho et al., 2010;Chung & Ferreira, 1999;Korolkovas & Burckhalter, 1988). ...
... Figura 1: Representação esquemática do conceito de pró-fármaco (F=fármaco, T=transportador, F-T = pró-fármaco). Fonte: Parise-Filho et al., 2010. Nesse contexto, o planejamento/desenvolvimento de pró-fármacos tem como principal objetivo superar diversos obstáculos ou barreiras biológicas que possam limitar o uso de um fármaco, tais como baixa solubilidade (hidro ou lipossolubilidade), sabor ou odor inadequado, irritação ou dor no local de aplicação, permeabilidade insuficiente pela barreira hemato-encefálica, extenso metabolismo présistêmico e baixa biodisponibilidade oral (Pereira, 2007;Chung & Ferreira, 1999). ...
... Nesse contexto, o planejamento/desenvolvimento de pró-fármacos tem como principal objetivo superar diversos obstáculos ou barreiras biológicas que possam limitar o uso de um fármaco, tais como baixa solubilidade (hidro ou lipossolubilidade), sabor ou odor inadequado, irritação ou dor no local de aplicação, permeabilidade insuficiente pela barreira hemato-encefálica, extenso metabolismo présistêmico e baixa biodisponibilidade oral (Pereira, 2007;Chung & Ferreira, 1999). Assim, a latenciação permite, entre outras vantagens, a reintrodução de substâncias anteriormente descartadas por suas propriedades indesejáveis e ainda o aprimoramento de novos fármacos, antes mesmo que sejam lançados na terapêutica (Parise-Filho et al., 2010;Chung et al., 2008;Rautio et al., 2008;Waller & George, 1989;Stella et al., 1985). ...
Prodrug design is an important tool in the drug discovery process, since many biological barriers that limit the use of a drug may be overcome by a prodrug precursor. This strategy allows the improvement of new drugs before they are marketed and also enables the reintroduction of substances previously discarded for their undesirable properties. Although clinical advantages of prodrug design are well-established, there are no studies demonstrating the economic benefits of using prodrugs rather than the intended drugs. The aim of this study was to elaborate a technical report on the relative cost of treatments carried out with prodrugs or with the related drugs. This study was intended to demonstrate the real importance of prodrug design as a guiding tool for drug development and the financial viability of the use of prodrugs. It was found that six of the analyzed prodrugs were financially advantageous compared to the actual drugs and that, even for the prodrugs that had a higher cost, the clinical advantage justified their therapeutic use.
