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Chemical structures of mefloquine, hydroxychloroquine and chloroquine. Mefloquine is a fluorinated derivative of hydroxychloroquine and chloroquine, exhibiting enhanced anti-COVID-19 activities.
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Over two years into the outbreak of COVID-19, the quest for effective and economical drugs has become starkly clear to reduce the risk of progression of coronavirus disease. A number of drugs have been investigated, and they can be taken orally at home and be used after exposure to SARS-CoV-2 or at the first sign of COVID-19. Fluorinated oral anti-...
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... HCl. Mefloquine (MFQ) is a fluorinated derivative of hydroxychloroquine (HCQ) originally used for antimalarial therapy and prophylaxis (Figure 8). It was identified as a potential drug to effectively treat patients with COVID-19 by Watashi and co-workers from the Tokyo University of Science and collaborating institutions in Japan in 2021. ...
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... Numerous published reviews underpin the medicinal significance of fluorine-containing compounds as the new chemical space in the design and development of small drug molecules to yield advanced agrochemicals and pharmaceuticals [29][30][31][32][33][34][35]. Moreover, fluorinated drugs recently played a very crucial role in controlling coronavirus disease 2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [33,35]. ...
... To address this issue, we focused on semisynthetic derivatives of 18βH-glycyrrhetinic acid (GA) obtained by transforming its native carboxyl group into a 1,2,4-oxadiazole fragment bearing different moieties at C-3, including aliphatic (1a−d, 2a−d), phenyl (1e−2e), and pyridine (1f−h, 2f−h) groups ( Figure 2). Additionally, considering that fluorination has great potential to enhance drug efficacy 23 and the presence of fluorine groups in the zosuquidar structure (Figure 1), GA derivatives containing fluorine-substituted phenyl rings (1i−k, 2i−k) were included in the study (Figure 2). Using molecular modeling, the interaction of GA derivatives with the active site of P-gp was explored, and the MDR reversal activity of the selected hit compound was thoroughly verified, providing new insights for further progress in the development of novel P-gp inhibitors. ...
Given the pharmacophore properties of the nitrogen-containing moiety in the molecular structure of P-glycoprotein (P-gp) inhibitors, we report the evaluation of the P-gp inhibitory and MDR reversal activities of 2g, a 3-meta-pyridin-1,2,4-oxadiazole derivative of 18βH-glycyrrhetinic acid. Through molecular docking, we have shown that 2g has the potential to directly interact with the transmembrane domain of P-gp with a low free binding energy (−10.2 kcal/mol). Using KB-8-5 human cervical carcinoma cells and RLS40 murine lymphosarcoma cells, both of which exhibit a multidrug-resistant (MDR) phenotype mediated by P-gp activation, we have shown that 2g, at nontoxic concentrations, effectively increased the intracellular accumulation of fluorescent P-gp substrates (rhodamine 123 or doxorubicin (DOX)), leading to a marked sensitization of the model cells to the cytotoxic effect of DOX. Considering the comparable activity of 2g with verapamil, a known P-gp inhibitor, 2g can be considered as a promising candidate for the development of agents capable of overcoming P-gp-mediated MDR in tumor cells.
... In this experiment, headspace gas chromatography was used to determine the residues of methyl alcohol and ethyl acetate in the bulk drug of Acetylisovaleryltylosin Tartrate. The method is simple, efficient, accurate and reliable, and meets the limited requirements of Pharmacopoeia [10,11]. ...
Acetylisovaleryltylosin Tartrate is a kind of macrolide antibiotic used for mycoplasma infection in pigs and chickens. The 2017 edition of “Quality Standard for Veterinary Drugs” clearly stipulates the characteristics, identification, inspection and content determination of Acetylisovaleryltylosin Tartrate. In this paper, firstly, the framework of computer chromatography and method verification are introduced. And then computer chromatography is applied to the determination of residual solvents in Acetylisovaleryltylosin Tartrate to process and analyze the output chromatographic data, and to determine the type and quantity of residual solvents. Finally, the determination of residual solvents in Acetylisovaleryltylosin Tartrate is actually analyzed. The residues of ethanol, acetone, dichloromethane, toluene, butyl acetate, and N-N dimethylformamide are determined by computer chromatography. The method is simple and has high column efficiency with accurate and reliable results, which meets the limit requirements of Pharmacopoeia. The chromatographic conditions and solution configuration in the residual solvent of Acetylisovaleryltylosin Tartrate are used to carry out a systematic applicability test to judge whether the blank solvent interferes with the reference substances of six residual solvents. In addition, the residual solvents in Acetylisovaleryltylosin Tartrate are analyzed before the test. Then computer gas chromatography is used to determine the six residual solvents in Acetylisovaleryltylosin Tartrate. The final result is that all six residual solvents meet the specified limits.
... The uracil derivative PSI-7672 (Fig. 23) can significantly inhibit HCV replication. The −CH 3 and −F moiety at the C-2′ position maintain the drug's potency and safety [171]. The negatively charged nature of substances containing phosphoric acid groups prevents the body from readily absorbing these substances [172]. ...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic since 2019, spreading rapidly and posing a significant threat to human health and life. With over 6 billion confirmed cases of the virus, the need for effective therapeutic drugs has become more urgent than ever before. RNA-dependent RNA polymerase (RdRp) is crucial in viral replication and transcription, catalysing viral RNA synthesis and serving as a promising therapeutic target for developing antiviral drugs. In this article, we explore the inhibition of RdRp as a potential treatment for viral diseases, analysing the structural information of RdRp in virus proliferation and summarizing the reported inhibitors’ pharmacophore features and structure–activity relationship profiles. We hope that the information provided by this review will aid in structure-based drug design and aid in the global fight against SARS-CoV-2 infection.
Graphical Abstract
... The importance of fluorine in medicinal chemistry cannot be undermined. [1][2][3][4][5] By incorporating fluorine into organic molecules, their physical, chemical, and biological properties can be drastically altered, making it vital for drug discovery. 6 In fact, 57 out of the Top 200 Small Molecule Pharmaceuticals by Retail Sales in 2021 contain fluorine. ...
Sodium triflinate (CF3SO2Na) is an inexpensive bench stable radical CF3 source that is often activated by external oxidants such as peroxides. However, despite the commercial accessibility of CF3SO2Na, the salt has never been applied to decarboxylative trifluoromethylation due to challenges in controlled cross-radical coupling. We report a redox-neutral approach to decarboxylative C(sp3) trifluoromethylation of carboxylic acid derivatives. Mechanistic inquiry is performed to address the limitations in scope.
... There are significant conformational biases that have a dramatic effect on biological activities. And, also fluorine atoms further add inter and intramolecular sites on fluoro compounds to interact properly, strongly, and selectively with different macromolecules like enzymes and receptors, etc. which further adds the flavor of fluoro-organic compounds (Purser et al. 2008;Zhang 2022). ...
... Recently, this compound was highlighted during COVID-19 tenure as a potential candidate to treat SARS-CoV-2. Favipiravir is an inhibitor of RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 virus first used in Wuhan at the very epicenter of the pandemic for the treatment of patients with mild to moderate COVID-19 disease (Zhang 2022). It is a kind of prodrug and converted into a more active form to its triphosphoribosylated (favipiravir-RTP), and thus selectively inhibiting viral RNA polymerase activity and preventing replication of the viral genome. ...
... In 2020, studies of this drug on moderate or severe COVID-19 patients, in combination with daclatasvir showed very encouraging results. Sofosbuvir inhibits SARS-CoV-2 replication in human hepatoma-derived (Huh-2) and Type II pneumocyte-derived (Calu-3) cells with EC 50 values of 6.2 and 9.5 μM, respectively (Zhang 2022). ...
During the last twenty years, organic fluorination chemistry established itself as an important tool to get a biologically active compound. This belief can be supported by the fact that every year, we are getting fluorinated drugs in the market in extremely significant numbers. Last year, also ten fluorinated drugs have been approved by FDA and during the COVID-19 pandemic, fluorinated drugs played a very crucial role to control the disease and saved many lives. In this review, we surveyed all ten fluorinated drugs approved by FDA in 2021 and all fluorinated drugs which were directly-indirectly used during the COVID-19 period, and emphasis has been given particularly to their synthesis, medicinal chemistry, and development process. Out of ten approved drugs, one drug pylarify, a radioactive diagnostic agent for cancer was approved for use in positron emission tomography imaging. Also, very briefly outlined the significance of fluorinated drugs through their physical, and chemical properties and their effect on drug development.Graphical abstract
... Many investigational anti-COVID-19 agents/medicines of the anti-RdRp category (e.g., favipiravir, 4′-fluorouridine, AT-527, and sofosbuvir) are characterized by their fluorinated skeletons. 27 Although fluorine atoms/ions are absent in almost all biological systems, they were recently used/benefited to tailor the pharmacological behaviors of some designed/repurposed compounds for an improvement of their anti-SARS-CoV-2/anti-COVID-19 therapeutic efficacies. 27 This therapeutic improvement may be specifically related to the fruitful effects fluorosubstitution exerts on the structural conformation, membrane permeability, metabolic directions, target protein binding, and overall pharmacokinetic properties of these compounds or drugs. ...
... 27 Although fluorine atoms/ions are absent in almost all biological systems, they were recently used/benefited to tailor the pharmacological behaviors of some designed/repurposed compounds for an improvement of their anti-SARS-CoV-2/anti-COVID-19 therapeutic efficacies. 27 This therapeutic improvement may be specifically related to the fruitful effects fluorosubstitution exerts on the structural conformation, membrane permeability, metabolic directions, target protein binding, and overall pharmacokinetic properties of these compounds or drugs. 27 In the therapeutic antiviral nucleoside mimicry strategy, we mainly draw on the similarity degree of the designed nucleoside-like compound with the normal endogenous human RNA nucleosides/nucleotides to mislead and deceive the SARS-CoV-2 RdRp (the nonstructural protein complex 12/7/8 or nsp12−nsp7−nsp8) and ExoN (the nonstructural protein complex 14/10 or nsp14−nsp10) enzymes. ...
... 27 This therapeutic improvement may be specifically related to the fruitful effects fluorosubstitution exerts on the structural conformation, membrane permeability, metabolic directions, target protein binding, and overall pharmacokinetic properties of these compounds or drugs. 27 In the therapeutic antiviral nucleoside mimicry strategy, we mainly draw on the similarity degree of the designed nucleoside-like compound with the normal endogenous human RNA nucleosides/nucleotides to mislead and deceive the SARS-CoV-2 RdRp (the nonstructural protein complex 12/7/8 or nsp12−nsp7−nsp8) and ExoN (the nonstructural protein complex 14/10 or nsp14−nsp10) enzymes. 28 In the current research work, we have tried to investigate the possible combined inhibitory activities of this new promising anti-COVID-19 agent, S-217622, on other SARS-CoV-2 proteins (i.e., other than the already-confirmed blocking activities on M pro ), like RdRp and ExoN enzymes, 29 as a novel effective approach to close all avenues for the coronavirus to reproduce with a view to synergistically and thoroughly battle COVID-19, SARS, MERS, and potentially all coming coronaviral infections and diseases of the next versions of the virus, hence also proving the universal broad-spectrum antiviral nature of this investigational agent on coronaviruses and their viral successors of the RNA type ( Figure 1A). ...
Lately, nitrogenous heterocyclic antivirals, such as nucleoside-like compounds, oxadiazoles, thiadiazoles, triazoles, quinolines, and isoquinolines, topped the therapeutic scene as promising agents of choice for the treatment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their accompanying ailment, the coronavirus disease 2019 (COVID-19). At the same time, the continuous emergence of new strains of SARS-CoV-2, like the Omicron variant and its multiple sublineages, resulted in a new defiance in the enduring COVID-19 battle. Ensitrelvir (S-217622) is a newly discovered orally active noncovalent nonpeptidic agent with potential strong broad-spectrum anticoronaviral activities, exhibiting promising nanomolar potencies against the different SARS-CoV-2 variants. S-217622 effectively and nonspecifically hits the main protease (Mpro) enzyme of a broad scope of coronaviruses. Herein, in the present computational/biological study, we tried to extend these previous findings to prove the universal activities of this investigational agent against any coronavirus, irrespective of its type, through synchronously acting on most of its main unchanged replication enzymes/proteins, including (in addition to the Mpro), e.g., the highly conserved RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN). Biochemical evaluation proved, using the in vitro anti-RdRp/ExoN bioassay, that S-217622 can potently inhibit the replication of coronaviruses, including the new virulent strains of SARS-CoV-2, with extremely minute in vitro anti-RdRp and anti-RdRp/ExoN half-maximal effective concentration (EC50) values of 0.17 and 0.27 μM, respectively, transcending the anti-COVID-19 drug molnupiravir. The preliminary in silico results greatly supported these biochemical results, proposing that the S-217622 molecule strongly and stabilizingly strikes the key catalytic pockets of the SARS-CoV-2 RdRp's and ExoN's principal active sites predictably via the nucleoside analogism mode of anti-RNA action (since the S-217622 molecule can be considered as a uridine analog). Moreover, the idealistic druglikeness and pharmacokinetic characteristics of S-217622 make it ready for pharmaceutical formulation with the expected very good clinical behavior as a drug for the infections caused by coronaviruses, e.g., COVID-19. To cut it short, the current critical findings of this extension work significantly potentiate and extend the S-217622's previous in vitro/in vivo (preclinical) results since they showed that the striking inhibitory activities of this novel anti-SARS-CoV-2 agent on the Mpro could be extended to other replication enzymes like RdRp and ExoN, unveiling the possible universal use of the compound against the next versions of the virus (i.e., disclosing the nonspecific anticoronaviral properties of this compound against almost any coronavirus strain), e.g., SARS-CoV-3, and encouraging us to rapidly start the compound's vast clinical anti-COVID-19 evaluations.
... PAXLOVID™ is an orally administered antiviral drug developed by Pfizer Inc. It contains nirmatrelvir (PF-07321332) (Fig. 11 a) and ritonavir (Fig. 11 b) [63]. Both PF-07321332 and ritonavir are protease inhibitors. ...
The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms of COVID-19 can range from asymptomatic to severe, which could lead to fatality. Like other pathogenic viruses, the infection of SARS-CoV-2 relies on binding its spike glycoprotein to the host receptor angiotensin-converting enzyme 2 (ACE 2). Molecular studies suggested that there is a high affinity between the spike glycoprotein and ACE 2 that might arise due to their hydrophobic interaction. This property is mainly responsible for making this virus highly infectious. Apart from this, the transmissibility of the virus, prolonged viability in certain circumstances, and rapid mutations also contributed to the current pandemic situation. Nanotechnology provides potential alternative solutions to combat COVID-19 with the development of i. nanomaterial-based COVID-19 detection technology, ii. nanomaterial-based disinfectants, iii. nanoparticle-based vaccines, and iv. nanoparticle-based drug delivery. Hence, this review provides diverse insight into understanding COVID-19.
Human cytomegalovirus (HCMV) is an important opportunistic pathogen that is the most
significant viral cause of congenital birth abnormalities and is responsible for a high morbidity and
death rate in immunocompromised patients. HCMV's rising severity and the limitations of current
vaccines in preventing infection highlight the urgent need for effective antiviral drugs. This study
aimed to identify small compounds using extensive & appropriate in-silico drug design techniques,
including molecular docking, Post-docking MM-GBSA, ADMET, MD simulation, PCA, and
DCCM were employed in this study capable of binding to the viral protease and inhibiting its
activity, thereby preventing proteolytic processing during capsid maturation. 3516 compounds
from life chemical were used in molecular docking, and the top four compounds having high
binding affinity and promising ADMET properties with life chemicals ID: F3407-0101 (CID:
49667672), F6559-3323 (CID: 121022124), F6456-1266 (CID: 71810903), and F3411-7969
(CID: 50785034). MD simulation was also used to assess the stability of the protein-ligand
complex structure. Finally, after MD simulation, principal component analysis (PCA), and
dynamic cross-correlation matrix (DCCM) analysis were performed using trajectories, and we can
suggest the best drug candidate which is CID: 50785034 (N-(3-fluoro-4-methylphenyl)-2-({7-oxo-
8-[(oxolan-2-yl) methyl]-5-thia-1,8,10,11-tetraazatricyclo [7.3.0.0^ {2,6}] dodeca-2(6),3,9,11-
tetraen-12-yl}sulfanyl)acetamide), another two compounds CID: 121022124, and CID: 71810903
which comes after CID: 50785034. All three compounds may have the potential to be developed
as a therapy option for HCMV infection.
