Table 1 - uploaded by Tamer M. Sakr
Content may be subject to copyright.
Contexts in source publication
Context 1
... The modifications in the base moiety of nucleoside analogs have resulted in a variety of therapeutic applications. There are different strategies in the modification of the nucleobase such as halogenation like 2`-3`-dideoxy-5-fluoro-3`-thiacytidine (Emtricitabine), 12 or as purine modification like 1,2,4- triazole-3-carboxamide analogue (Ribavirin), 13 which is used to stop viral RNA synthesis ( Table 1). L-nucleosides, for a long time, it was assumed that nucleoside analogs have been only D-configuration and could exhibit biological activity owing to the believed stereospecificity of enzymes in the living system. ...
Context 2
... analogs have been the drugs of choice in the treatment of several diseases caused by herpes simplex virus (HSV), human cytomegalovirus (HCMV), varicella zoster virus (VZV), human immunodeficiency virus type 1 (HIV-1) and human hepatitis B (HBV) and C (HCV) virus 16 . Currently, there are over twenty FDA approved nucleoside and nucleotide analogs that are used as antiviral agents for several infections such as different types of viral hepatitis, human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) and herpes virus infections, 16 ( Table 1). ...
Context 3
... 2`-deoxynucleosides as Idoxuridne (IDU), 18 Trifluridine (TFT), 19 Edoxudine (EDU), 20 Vidarabine and Brivudine 21 (BVDU) have been used for the treatment of herpes viruses as DNA polymerase inhibitors. Acyclic nucleosides as Acyclovir (ACV), Ganciclovir (GCV), Valaciclovir (VACV), Cidofovir (CDV), Valganciclovir (VGCV), Penciclovir (PCV) and Famciclovir (FCV) have been used for the treatment of herpes viruses ( Table 1). 22 The 2`,3`-dideoxynucleosides (ddNs) have proved to be the most effective therapeutic agents against HIV because the absence of 3`-hydroxyl group can be lead to the termination of DNA sequence such as Zidovudine (AZT), Didanosine (ddI), Zalcitabine (ddC), Stazudine (d4T) 23 and Abacavir 24 (ABV). ...
Similar publications
Formyl glycals are the versatile synthetic intermediates and can serves as precursor for the synthesis of various C and N-nucleosides. Due to the presence of electron donating and electron withdrawing character on formyl sugars which makes the molecule more susceptible to nucleophilic attack. Utilizing same strategy, we propose the synthesis of div...
Citations
... Purine and its derived nucleobases adenine and guanine (Table 1) are basic structures of a group of various micropollutants. Analogues of these molecules are used as antiviral compounds such as acyclovir and penciclovir (Table 1) (Clercq and Li, 2016;Geraghty et al., 2021;Mahmoud et al., 2018). The research on new structurally related antivirals increased in the last decades and shows the importance of this structural group (Geraghty et al., 2021) whose application in antiviral treatment rises (Bacon et al., 2003). ...
... Purine is the basic structure of the nucleobases adenine and guanine (Gossauer, 2006). A large group of antiviral agents regularly detected in wastewaters and the aquatic environment (Peng et al., 2014;Prasse et al., 2010;Swanepoel et al., 2015) bases upon these two structures (Mahmoud et al., 2018). Biological degradation of the pharmaceuticals can lead to the formation of structurally-related metabolites still including the fundamental double-ring moiety (Funke et al., 2016;Prasse et al., 2011). ...
Ozonation of micropollutants strongly depends on the water matrix. Natural organic matter is known to highly affect the hydroxyl radical exposure due to radical promoting and inhibiting effects. Other important matrix components in ozonation are carbonate species which scavenge hydroxyl radicals. However, additional factors such as the formation of other radicals might also play a role but are generally not covered in research or considered in modelling of micropollutant degradation. Hence, the ozonation of purine derivatives, the basic structure of various antiviral micropollutants, in different artificial water matrices is investigated in this study with focus on the impact of natural organic matter and increasing alkalinity on the degradation and product formation. The degradation of purine and adenine is inhibited by bicarbonate in the water matrix due to the anion's scavenging of hydroxyl radicals. This effect is already observed for low bicarbonate concentrations of 0.3 mM. However, formed carbonate radicals contribute to the compounds' degradation and also affect the stability of transformation products. This effect gains in relevance with increasing alkalinity and needs consideration in evaluating ozonation of very hard waters. Three ozonation products are evaluated in detail, which are affected by the matrix due to impacts on ozone stability, hydroxyl radical yield and carbonate radical formation. One product of adenine with the mass 147 was reported for the first time and only occurs in presence of matrix components. Under typical water treatment conditions rough predictions of pollutants' degradation are possible by the Rct concept using ozone and hydroxyl radical exposures. However, other reactive species such as carbonate radicals are not considered leading to deviations between modelled and experimental data at extreme conditions such as industrial wastewater. A general correlation between the Rct and the fraction f of hydroxyl radicals scavenged by bicarbonate (ln(Rct) = - 5.9 × f - 16.3) calculated from the concentration of organic matter and alkalinity was observed for various water samples allowing the estimation of micropollutant degradation during ozone treatment at moderate conditions by simple organic and inorganic carbon measurements.
... To better contextualize this work, it is useful to focus our attention on another successful class of antitumor/antiviral drugs, nucleos(t)ide analogs (NAs). Common nucleos(t)ide antimetabolites are structurally similar to natural nucleos(t)ides and are widely used in the treatment of cancer/viral diseases [28][29][30][31][32][33][34][35][36]. Developed over the past fifty years, NAs can interfere with nucleic acid production and functionality, thereby impeding cancer cells'/viruses' growth and survival [37,38]. ...
... Resistance phenomena to NAs drugs can arise from various factors, including inefficient uptake and faulty apoptosis induction [42,43]. This drug family is now considered essential for creating innovative drugs capable of combating new epidemic viruses [28,33,41,[44][45][46][47]. The related research activities were boosted by the pandemic worldwide diffusion of pathogenic viruses (HIV, hepatitis, SARS, etc.), producing the approval of many new protocols for the treatment of viral diseases, including NAs [31,48]. ...
In this work, we elucidated some key aspects of the mechanism of action of the cis-platin anticancer drug, cis-[Pt(NH3)2Cl2], involving direct interactions with free nucleotides. A comprehensive in silico molecular modeling analysis was conducted to compare the interactions of Thermus aquaticus (Taq) DNA polymerase with three distinct N7-platinated deoxyguanosine triphosphates: [Pt(dien)(N7-dGTP)] (1), cis-[Pt(NH3)2Cl(N7-dGTP)] (2), and cis-[Pt(NH3)2(H2O)(N7-dGTP)] (3) {dien = diethylenetriamine; dGTP = 5-(2-deoxy)-guanosine-triphosphate}, using canonical dGTP as a reference, in the presence of DNA. The goal was to elucidate the binding site interactions between Taq DNA polymerase and the tested nucleotide derivatives, providing valuable atomistic insights. Unbiased molecular dynamics simulations (200 ns for each complex) with explicit water molecules were performed on the four ternary complexes, yielding significant findings that contribute to a better understanding of experimental results. The molecular modeling highlighted the crucial role of a specific α-helix (O-helix) within the fingers subdomain, which facilitates the proper geometry for functional contacts between the incoming nucleotide and the DNA template needed for incorporation into the polymerase. The analysis revealed that complex 1 exhibits a much lower affinity for Taq DNA polymerase than complexes 2-3. The affinities of cisplatin metabolites 2-3 for Taq DNA polymerase were found to be quite similar to those of natural dGTP, resulting in a lower incorporation rate for complex 1 compared to complexes 2-3. These findings could have significant implications for the cisplatin mechanism of action, as the high intracellular availability of free nucleobases might promote the competitive incorporation of platinated nucleotides over direct cisplatin attachment to DNA. The study's insights into the incorporation of platinated nucleotides into the Taq DNA polymerase active site suggest that the role of platinated nucleotides in the cisplatin mechanism of action may have been previously underestimated.
... [1] Interestingly, biological activity, as well as the chemical and physical properties of nucleoside derivatives, can be tuned remarkably by the simple alteration of the sugar moiety of a nucleoside with different substituents and heteroatoms, along with others. [2] Moreover, nucleoside derivatives have immense clinical importance as medicinal agents because of their antiviral and anticancer activities [3] ; they have been the drug of choice to treat various viral diseases, such as Ebola, Dengue, and Zika. [4] Additionally, 2′-deoxynucleosides such as deoxyuridine, trifluridine, doxudine, vidarabine, and brivudine, have been used to treat herpes virus infections. ...
... The COSY spectrum of analog (2) showed that the starting point could well be the signal from the Ar-NH proton, which is the most downfield and can be readily assigned. Thus, the signal from Ar-NH at the bottom left of the diagonal has a cross-peak labeled as Ar-NH, H-3′ connecting it to the signal from H-3′. ...
... precursor analog (2) (Table 1) clearly demonstrated the attachment of myristoyl groups at C-5′ positions of thymidine. Assignments of the signals by analyzing its COSY, HSQC, and HMBC spectral experiments ( Fig. 1) along with the 13 C NMR spectrum confirmed the structure as 5′-O-(myristoyl)thymidine (2). ...
Nucleoside analogs are an important, well-established class of clinically useful medicinal agents that exhibit potent antimicrobial activity. Thus, we designed to explore the synthesis and spectral characterization of 5'-O-(myristoyl)thymidine esters (2-6) for in vitro antimicrobial, molecular docking, molecular dynamics, SAR, and POM analyses. An unimolar myristoylation of thymidine under controlled conditions furnished the 5'-O-(myristoyl)thymidine and it was further converted into four 3'-O-(acyl)-5'-O-(myristoyl)thymidine analogs. The chemical structures of the synthesized analogs were ascertained by analyzing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests along with PASS, prediction indicated expectant antibacterial functionality of these thymidine esters compared to the antifungal activities. In support of this observation, their molecular docking studies have been performed against lanosterol 14α-demethylase (CYP51A1) and Aspergillus flavus (1R51) and significant binding affinities and non-bonding interactions were observed. The stability of the protein-ligand complexes was monitored by a 100 ns MD simulation and found the stable conformation and binding mode in a stimulating environment of thymidine esters. Pharmacokinetic predictions were studied to assess their ADMET properties and showed promising results in silico. SAR investigation indicated that acyl chains, lauroyl (C-12) and myristoyl (C-14), combined with deoxyribose, were most effective against the tested bacterial and fungal pathogens. The POM analyses provide the structural features responsible for their combined antibacterial/antifungal activity and provide guidelines for further modifications, with the aim of improving each activity and selectivity of designed drugs targeting potentially drug-resistant microorganisms. It also opens avenues for the development of newer antimicrobial agents targeting bacterial and fungal pathogens.
... These active agents are among others acyclovir and penciclovir. 10,11 Acyclovir is recovered in urine excretion by up to 80% and in the form of one metabolite with an unchanged ring system. 12 Generally, the considered analogues are known to be highly degradable in conventional wastewater treatment by around 90%. ...
... 14−18 Adenine analogues are, for example, applied in the treatment of hepatitis B virus or human immunodeficiency virus. 19 Common agents are adefovir and tenofovir, 10 which are excreted unaltered in the urine up to 40%. 20,21 The latter antiviral is known to be degradable in wastewater treatment. ...
... Under outbreak conditions, the use of drugs in aquaculture is indispensable, however, there are few drugs registered for use in fish, which leads to the indiscriminate use of various chemical substances (Carraschi et al., 2017;Charlie-Silva et al., 2020). The study of clinical safety in fish becomes relevant, and this happens through hematological and biochemical tests, in which they are essential parameters to assess the physiological condition of fish (Mahmoud et al. 2018) considering the use of pharmaceutical molecules in aquaculture. ...
This study aimed to evaluate the clinical safety of doxycycline treatment (Sandoz Pharmacetical Industry from Brazil Ltd.), administered orally incorporated into the feed of Nile tilapia, Oreochromis niloticus. For this purpose, 75 Nile tilapia (± 300g) from the same spawning were randomly distributed in 15 tanks (n=5), containing 100 L of water each, supplied with running water free from chlorine, to establish the following treatments: T0 (Control - not treated with doxycycline); T1, T2, T3 and T4 (treated with 10, 20, 40 and 80mg of doxycycline/kg of body weight, respectively), in which 5 animals per treatment were sampled in 3 periods: 2, 4 and 8 days post-treatment (DPT). Blood samples were collected for hemogram determination and serum biochemical evaluation, as well as spleen, liver and kidneys (cranial and caudal) for somatic and histopathological evaluation. The results showed no significant difference among treatments in the serum values of creatinine, total protein, cholesterol, triglycerides, globulin, glycemia and alkaline phosphatase enzyme activity. However, serum levels of AST (aspartate aminotransferase) were significantly higher (P<0.05) in animals treated with 80 mg of doxycycline in the longest period of treatment (8 days). In the hematological evaluation of tilapia treated with doxycycline, no significant changes (P>0.05) were observed in erythrocyte counts, hematocrit, MCV, HC and CHCM values. Doxycycline-treated tilapia did not present significant difference in the somatic analysis of spleen, liver and kidney when compared to control group. Therefore, the results demonstrated the clinical safety of oral treatment with doxycycline at doses of 10, 20, 40 and 80 mg/kg of b.w., although transient changes in liver functionality were observed after eight days of treatment with the dose of 80mg/kg.
... Obviously, the development of safe and highly selective broad-spectrum antiviral agents is a must if we want to combat new, resistant forms of known viral infections. Of particular interest are synthetic analogs of natural nucleosides and nucleotides, because they have been used for a long time to diagnose and treat various infectious diseases and have also retain considerable biological and pharmaceutical potency [4,5]. ...
1,4-Pyrazine-3-carboxamide-based antiviral compounds have been under intensive study for the last 20 years. One of these compounds, favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide, T-705), is approved for use against the influenza infection in a number of countries. Now, favipiravir is being actively used against COVID-19. This review describes the in vivo metabolism of favipiravir, the mechanism of its antiviral activity, clinical findings, toxic properties, and the chemical synthesis routes for its production. We provide data on the synthesis and antiviral activity of structural analogs of favipiravir, including nucleosides and nucleotides based on them.
... More critically, nucleosides and nucleotide analogs have been used as the most prominent antiviral drugs for the treatment of herpes simplex virus (HSV), human immunodeficiency virus type 1 (HIV-1), and human hepatitis B (HBV). More than 20 FDA-approved nucleoside and nucleotide analogs are used as antiviral agents for multiple infections (43,44). Therefore, researchers have been devoted to constructing nucleoside/nucleoside analog-producing engineered strains. ...
The transport of nucleosides and their homeostasis within the cell are essential for growth and proliferation. Here, we have identified a novel transcription factor, NupR, which, to our knowledge, is the first GntR family transcription factor primarily involved in the regulation of nucleoside transport.
... Nucleoside analogs are the subunits of DNA and RNA, and structurally they consist of a sugar moiety linked to a nitrogen base through an N-β-glycosidic bond. Interestingly, biological activity, as well as the chemical and physical properties of nucleoside analog, can be tuned remarkably by the simple alteration of the sugar moiety of a nucleoside with different substituents and heteroatoms, among others [2]. The nucleoside analogs usually show antiviral activity by inhibiting viral replication through the blockage of cellular division; impairment of DNA/RNA synthesis or inhibition of cellular or viral enzyme activity. ...
... The COSY spectrum of compound (2) showed that the starting point could well be the signal from Ar-NH proton which is the most downfield and therefore readily assigned. Thus the signal from Ar-NH at the bottom left of the diagonal has a cross-peak labelled as Ar-NH, H-5b connecting it to the signal from H-5b. ...
... The importance of MEP lies in the fact that it simultaneously shows the molecular size and shape, as well as positive, negative and neutral electrostatic potential regions in terms of colour grading, which is very useful in the research of molecular structure, along with the physicochemical properties relationship [68]. Molecular electrostatic potential (MEP) was calculated to forecast the reactive sites for the electrophilic and nucleophilic attack of the optimized structure of thymidine (1) and analogs (2)(3)(4)(5)(6). The different values of electrostatic potential are represented by different colours, with potential increases in the order red < orange < yellow < green < blue. ...
Nucleoside precursors and nucleoside analogs occupy an important place in the treatment of viral respiratory pathologies, especially during the current COVID-19 pandemic. From this perspective, the present study has been designed to explore and evaluate the synthesis and spectral characterisation of 5́-O-(lauroyl) thymidine analogs 2–6 with different aliphatic and aromatic groups through comprehensive in vitro antimicrobial screening, cytotoxicity assessment, physicochemical aspects, molecular docking and molecular dynamics analysis, along with pharmacokinetic prediction. A unimolar one-step lauroylation of thymidine under controlled conditions furnished the 5́-O-(lauroyl) thymidine and indicated the selectivity at C-5́ position and the development of thymidine based potential antimicrobial analogs, which were further converted into four newer 3́-O-(acyl)-5́-O-(lauroyl) thymidine analogs in reasonably good yields. The chemical structures of the newly synthesised analogs were ascertained by analysing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi, along with the prediction of activity spectra for substances (PASS), indicated promising antibacterial functionality for these thymidine analogs compared to antifungal activity. In support of this observation, molecular docking experiments have been performed against the main protease of SARS-CoV-2, and significant binding affinities and non-bonding interactions were observed against the main protease (6LU7, 6Y84 and 7BQY), considering hydroxychloroquine (HCQ) as standard. Moreover, the 100 ns molecular dynamics simulation process was performed to monitor the behaviour of the complex structure formed by the main protease under in silico physiological conditions to examine its stability over time, and this revealed a stable conformation and binding pattern in a stimulating environment of thymidine analogs. Cytotoxicity determination confirmed that compounds were found less toxic. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. The POM analysis shows the presence of an antiviral (O1δ-, O2δ-) pharmacophore site. Overall, the current study should be of great help in the development of thymidine-based, novel, multiple drug-resistant antimicrobial and COVID-19 drugs.
... There have been numerous reviews of monophosph(on)ate prodrugs, often focussing on the clinically approved prodrugs or those in clinical trials. [10][11][12][13][123][124][125][126] As a result, only a brief overview will be given here. ...
Pyrophosphates have important functions in living systems and thus pyrophosphate-containing molecules and their more stable bisphosphonate analogues have the potential to be used as drugs for treating many diseases including cancer and viral infections. Both pyrophosphates and bisphosphonates are polyanionic at physiological pH and, whilst this is essential for their biological activity, it also limits their use as therapeutic agents. In particular, the high negative charge density of these compounds prohibits cell entry other than by endocytosis, prevents transcellular oral absorption and causes sequestration to bone. Therefore, prodrug strategies have been developed to temporarily disguise the charges of these compounds. This review examines the various systems that have been used to mask the phosphorus-containing moieties of pyrophosphates and bisphosphonates and also illustrates the utility of such prodrugs.
