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1.
Chem Zvesti ; : 1, 2022 Jun 04.
Article in English | MEDLINE | ID: covidwho-1942864

ABSTRACT

[This retracts the article DOI: 10.1007/s11696-021-01640-9.].

2.
ACS omega ; 7(25):21385-21396, 2022.
Article in English | EuropePMC | ID: covidwho-1918878

ABSTRACT

Analogues and derivatives of natural nucleosides/nucleotides are considered among the most successful bioactive species of drug-like compounds in modern medicinal chemistry, as they are well recognized for their diverse and efficient pharmacological activities in humans, especially as antivirals and antitumors. Coronavirus disease 2019 (COVID-19) is still almost incurable, with its infectious viral microbe, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continuing to wreak devastation around the world. This global crisis pushed all involved scientists, including drug discoverers and clinical researchers, to try to find an effective and broad-spectrum anti-COVID-19 drug. Didanosine (2′,3′-dideoxyinosine, DDI) is a synthetic inosine/adenosine/guanosine analogue and highly active antiretroviral therapeutic agent used for the treatment of human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS). This potent reverse-transcriptase inhibitor is characterized by proven strong pharmacological effects against the viral genome, which may successfully take part in the effective treatment of SARS-CoV-2/COVID-19. Additionally, targeting the pivotal SARS-CoV-2 replication enzyme, RNA-dependent RNA polymerase (RdRp), is a very successful tactic to combat COVID-19 irrespective of the SARS-CoV-2 variant type because RdRps are broadly conserved among all SARS-CoV-2 strains. Herein, the current study proved for the first time, using the in vitro antiviral evaluation, that DDI is capable of potently inhibiting the replication of the novel virulent progenies of SARS-CoV-2 with quite tiny in vitro anti-SARS-CoV-2 and anti-RdRp EC50 values of around 3.1 and 0.19 μM, respectively, surpassing remdesivir together with its active metabolite (GS-441524). Thereafter, the in silico computational interpretation of the biological results supported that DDI strongly targets the key pocket of the SARS-CoV-2 RdRp main catalytic active site. The ideal pharmacophoric characteristics of the ligand DDI make it a typical inhibiting agent of SARS-CoV-2 multiplication processes (including high-fidelity proofreading), with its elastic structure open for many kinds of derivatization. In brief, the present results further uphold and propose the repurposing potentials of DDI against the different types of COVID-19 and convincingly motivate us to quickly launch its extensive preclinical/clinical pharmacological evaluations, hoping to combine it in the COVID-19 therapeutic protocols soon.

3.
Chem Zvesti ; : 1-17, 2021 May 16.
Article in English | MEDLINE | ID: covidwho-1877948

ABSTRACT

ABSTRACT: Specific inhibition of the viral RNA-dependent RNA polymerase (RdRp) of the newly-emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising strategy for developing highly potent medicines for coronavirus disease 2019 (COVID-19). However, almost all of the reported viral RdRp inhibitors (either repurposed drugs or new antiviral agents) lack selectivity against the SARS-CoV-2 RdRp. Herein, I discovered a new favipiravir derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). Based on the significant reduction in the in vitro SARS-CoV-2 replication/copies, strong computational cyanorona-20 ligand-RdRp protein interactions, and anti-RdRp activity of the parent favipiravir drug, SARS-CoV-2 inhibition is thought to be mediated through the coronaviral-2 RdRp inhibition. This promising selective anti-COVID-19 compound is also, to the best of our knowledge, the first bioactive derivative of favipiravir, the known antiinfluenza and antiviral drug. This new nucleoside analog was designed, synthesized, characterized, computationally studied (through pharmacokinetic calculations along with computational molecular modeling and prediction), and biologically evaluated for its anti-COVID-19 activities (through a validated in vitro anti-COVID-19 assay). The results of the biological assay showed that cyanorona-20 surprisingly exhibited very significant anti-COVID-19 activity (anti-SARS-CoV-2 EC50 = 0.45 µM), and, in addition, it could be also a very promising lead compound for the design of new anti-COVID-19 agents. Cyanorona-20 is a new favipiravir derivative with promise for the treatment of SARS-CoV-2 infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11696-021-01640-9.

4.
ACS Omega ; 7(3): 2960-2969, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1636721

ABSTRACT

Nucleoside analogues are among the most successful bioactive classes of druglike compounds in pharmaceutical chemistry as they are well-known for their numerous effective bioactivities in humans, especially as antiviral and anticancer agents. Coronavirus disease 2019 (COVID-19) is still untreatable, with its causing virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continuing to wreak havoc on the ground everywhere. This complicated international situation urged all concerned scientists, including medicinal chemists and drug discoverers, to search for a potent anti-COVID-19 drug. Cordycepin (3'-deoxyadenosine) is a known natural adenosine analogue of fungal origin, which could also be synthetically produced. This bioactive phytochemical compound is characterized by several proven strong pharmacological actions that may effectively contribute to the comprehensive treatment of COVID-19, with the antiviral activities being the leading ones. Some new studies predicted the possible inhibitory affinities of cordycepin against the principal SARS-CoV-2 protein targets (e.g., SARS-CoV-2 spike (S) protein, main protease (Mpro) enzyme, and RNA-dependent RNA polymerase (RdRp) enzyme) based on the computational approach. Interestingly, the current research showed, for the first time, that cordycepin is able to potently inhibit the multiplication of the new resistant strains of SARS-CoV-2 with a very minute in vitro anti-SARS-CoV-2 EC50 of about 2 µM, edging over both remdesivir and its active metabolite GS-441524. The ideal pharmacophoric features of the cordycepin molecule render it a typical inhibitor of SARS-CoV-2 replication, with its flexible structure open for most types of derivatization in the future. Briefly, the current findings further support and suggest the repurposing possibility of cordycepin against COVID-19 and greatly encourage us to confidently and rapidly begin its preclinical/clinical evaluations for the comprehensive treatment of COVID-19.

5.
Curr Res Pharmacol Drug Discov ; 2: 100055, 2021.
Article in English | MEDLINE | ID: covidwho-1401402

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has undoubtedly become a global crisis. Consequently, discovery and identification of new or known potential drug candidates to solve the health problems caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become an urgent necessity. This current research study sheds light on the possible direct repurposing of the antirheumatic drug teriflunomide to act as an effective and potent anti-SARS-CoV-2 agent. Herein, an interesting computational molecular docking study of teriflunomide, to investigate and evaluate its potential inhibitory activities on the novel coronaviral-2 RNA-dependent RNA polymerase (nCoV-RdRp) protein, was reported. The docking procedures were accurately carried out on nCoV-RdRp (with/without RNA) using the COVID-19 Docking Server, through adjusting it on the small molecule docking mode. Remdesivir and its active metabolite (GS-441524) were used as the active references for the comparison and evaluation purpose. Interestingly, the computational docking analysis of the best inhibitory binding mode of teriflunomide in the binding pocket of the active site of the SARS-CoV-2 RdRp revealed that teriflunomide may exhibit significantly stronger inhibitory binding interactions and better inhibitory binding affinities (teriflunomide has considerably lower binding energies of -9.70 and -7.80 â€‹kcal/mol with RdRp-RNA and RdRp alone, respectively) than both references. It was previously reported that teriflunomide strongly inhibits the viral replication and reproduction through two mechanisms of action, thus the results obtained in the present study surprisingly support the double mode of antiviral action of this antirheumatic ligand. In conclusion, the current research paved the way to practically prove the hypothetical theory of the promising abilities of teriflunomide to successfully attack the SARS-CoV-2 particles and inhibit their replication in a triple mode of action through integrating the newly-discovered nCoV-RdRp-inhibiting properties with the previously-known two anticoronaviral mechanisms of action. Based on the previous interesting facts and results, the triple SARS-CoV-2/sextet COVID-19 attacker teriflunomide can further undergo in vitro/in vivo anti-COVID-19 assays together with preclinical/clinical studies and trials in an attempt to evaluate and prove its comprehensive pharmacological activities against the different SARS-CoV-2 strains to be effectively used in COVID-19 therapy in the very near future.

6.
Sexologies ; 2021.
Article in English | ScienceDirect | ID: covidwho-1347828

ABSTRACT

Objectives: Mortal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been known to cause many signs/symptoms reported by authors from Wuhan (China), but none of these early reports and papers has specifically included male sexual dysfunction as one of these major symptoms until mid-2020. The primary aim of this interesting research study is to examine and investigate the possible relationship between the coronavirus disease 2019 (COVID-19) and the sudden temporary sexual dysfunction in adult males during the pandemic. Some other secondary hypotheses will be also investigated. Material and Methods: With the onset of COVID-19 pandemic, we have noticed an intense increase in the number of male patients who have presented to andrologists with new sudden onset of various moderate to severe sexual dysfunction problems (e.g., erectile dysfunction/impotence, infertility, and hypogonadism) in Egypt and USA hospitals and clinics along with telemedicine consultations. The high frequency with which patients present with these sexual problems was extremely unusual. Herein, we described patients who have presented with unexpected moderate to complete loss of their sexual abilities (which did not happen before in that unreasonable way) with the presence of normal and intact sexual desire during a five-week period of the COVID-19 pandemic. Results: Most of these male patients had either no COVID-19 symptoms or very mild-to-moderate respiratory symptoms known in COVID-19 patients. Although most of patients had normal otolaryngologic exam results, but, surprisingly, almost all tested positive for COVID-19. A strong relationship between COVID-19 and sudden sexual dysfunction in men should certainly be considered and investigated during the pandemic. Conclusion: We mainly deduced, for the first time, that SARS-CoV-2 invasion of the male's reproductive system may directly cause sudden temporary sexual dysfunction problems ranged from unobserved moderate to irritatingly severe and complete in their pathologic outcomes, hence sex should be avoided during the pandemic. Resumen Objectifs: Le coronavirus 2 du syndrome respiratoire aigu sévère mortel (SARS-CoV-2) est connu pour provoquer de nombreux signes/symptômes rapportés par des auteurs de Wuhan (Chine), mais aucun de ces premiers rapports et articles n'a spécifiquement inclus le dysfonctionnement sexuel masculin parmi ceux-ci symptômes majeurs jusqu'à la mi-2020. L'objectif principal de cette étude de recherche intéressante est d'examiner et d'étudier la relation possible entre la maladie à coronavirus 2019 (COVID-19) et le dysfonctionnement sexuel temporaire soudain chez les hommes adultes pendant la pandémie. D'autres hypothèses secondaires seront également étudiées. Matériel et méthodes: Avec le début de la pandémie de COVID-19, nous avons remarqué une augmentation intense du nombre de patients de sexe masculin qui se sont présentés aux andrologues avec une nouvelle apparition soudaine de divers problèmes de dysfonction sexuelle modérée à sévère (par exemple, dysfonction érectile/impuissance, infertilité et hypogonadisme) dans les hôpitaux et cliniques d'Égypte et des États-Unis ainsi que des consultations de télémédecine. La fréquence élevée avec laquelle les patients présentent ces problèmes sexuels était extrêmement inhabituelle. Ici, nous avons décrit des patients qui ont présenté une perte inattendue modérée à complète de leurs capacités sexuelles (ce qui ne s'était pas produit auparavant de cette manière déraisonnable) avec la présence d'un désir sexuel normal et intact pendant une période de cinq semaines de la pandémie de COVID-19. Résultats: La plupart de ces patients de sexe masculin ne présentaient aucun symptôme COVID-19 ou des symptômes respiratoires très légers à modérés connus chez les patients COVID-19. Bien que la plupart des patients aient eu des résultats d'examen otolaryngologiques normaux, mais, étonnamment, presque tous ont été testés positifs pour COVID-19. Une forte relation entre COVID-19 et un dysfonctionnement sexuel soudain chez les hommes devrait certainement être envisagée et étudiée pendant la pandémie. Conclusion: Nous avons principalement déduit, pour la première fois, que l'invasion par le SARS-CoV-2 du système reproducteur de l'homme peut directement causer des problèmes de dysfonctionnement sexuel temporaires soudains allant de modérés non observés à irritants graves et complets dans leurs résultats pathologiques, par conséquent, les relations sexuelles doivent être évitées pendant le pandémie.

7.
J Mol Struct ; 1246: 131106, 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1313340

ABSTRACT

Polyhydroxyphenols and nitrogenous heterocyclics are two of the most powerful active species of molecules in pharmaceutical chemistry, as each of them is renowned for its various bioactivities for humans. One of their outstanding actions is the antiviral activities, which clearly appear if the principal functional entities of both classes meet into one compound. The recent COVID-19 pandemic pushed us to computationally sift and assess our small library of synthetic 2-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazoles against the main coronaviral protein/enzymatic targets. Surprisingly, few ligands exhibited interesting low binding energies (strong inhibitory affinities) with some SARS-CoV-2 proteins, mainly the pivotal enzyme RNA-dependent RNA polymerase (nCoV-RdRp). One of these compounds was Taroxaz-104 (5,5'-{5,5'-[(1R,2R)-1,2-dihydroxyethane-1,2-diyl]bis(1,3,4-oxadiazole-5,2-diyl)}dibenzene-1,2,3-triol), which presented lower binding free energies of about -10.60 and -9.10 kcal/mol (as compared to the reference agent, GS-443902, which presented about -9.20 and -7.90 kcal/mol) with nCoV-RdRp-RNA and nCoV-RdRp alone, respectively. Extensive molecular modeling examination disclosed the potent Taroxaz-104 inhibition of one of the possible active/allosteric sites of nCoV-RdRp, since Taroxaz-104 molecule interacts with at least seven main amino acids of the presumed pocket/cavity of this nCoV-RdRp active site. The effective repurposing of Taroxaz-104 molecule was attained after the satisfactorily interesting results of the anti-COVID-19 bioassay were secured, since these data demonstrated that Taroxaz-104 showed very efficient anti-COVID-19 actions (anti-SARS-CoV-2 EC50 = 0.42 µM) with specific promising efficacy against the new SARS-CoV-2 strains. Additional research studies for the progress of Taroxaz-104 and other related polyphenolic 2,5-disubstituted-1,3,4-oxadiazole analogs as successful anti-SARS-CoV-2 medications, via, e.g., preclinical/clinical trials, are pressingly required.

8.
Int Immunopharmacol ; 98: 107831, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1313172

ABSTRACT

Explicit hindrance and blockade of the viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is considered one of the most promising and efficient approaches for developing highly potent remedies for COVID-19. However, almost all of the reported viral RdRp inhibitors (either repurposed or new antiviral drugs) lack specific selectivity against the novel coronaviral RdRp and still at a beginning phase of advancement. Herein, I discovered and introduce a new pyrazine derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 RdRp inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). This promising selective specific anti-COVID-19 compound is also deemed to be the first distinctive derivative of favipiravir. Cyanorona-20, the unprecedented nucleoside/nucleotide analog, was designed, synthesized, characterized, computationally studied, and biologically evaluated for its anti-COVID-19 actions (through a precise in vitro anti-COVID-19 assay). The results of the biological assay displayed that cyanorona-20 surprisingly exhibited very high and largely significant anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.45 µM), and, in addition, it could be also a very promising guide and lead compound for the design and synthesis of new anti-SARS-CoV-2 and anti-COVID-19 agents through structural modifications and further computational studies. Further appraisal for the improvement of cyanorona-20 medication is a prerequisite requirement in the coming days. In a word, the ascent of the second member (cyanorona-20 "Corona Antidote") of the novel and promising class of anti-COVID-19 pyrazine derivatives would drastically make a medical uprising in the pharmacotherapeutic treatment regimens and protocols of the recently-emerged SARS-CoV-2 infection and its accompanying COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Enzyme Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Virus Replication/drug effects , Antiviral Agents/chemical synthesis , COVID-19/diagnosis , COVID-19/virology , Computer-Aided Design , Drug Design , Enzyme Inhibitors/chemical synthesis , Host-Pathogen Interactions , Humans , Molecular Docking Simulation , Molecular Structure , Molecular Targeted Therapy , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/growth & development , Structure-Activity Relationship
9.
Chem Zvesti ; : 1-17, 2021 May 16.
Article in English | MEDLINE | ID: covidwho-1237549

ABSTRACT

ABSTRACT: Specific inhibition of the viral RNA-dependent RNA polymerase (RdRp) of the newly-emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising strategy for developing highly potent medicines for coronavirus disease 2019 (COVID-19). However, almost all of the reported viral RdRp inhibitors (either repurposed drugs or new antiviral agents) lack selectivity against the SARS-CoV-2 RdRp. Herein, I discovered a new favipiravir derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). Based on the significant reduction in the in vitro SARS-CoV-2 replication/copies, strong computational cyanorona-20 ligand-RdRp protein interactions, and anti-RdRp activity of the parent favipiravir drug, SARS-CoV-2 inhibition is thought to be mediated through the coronaviral-2 RdRp inhibition. This promising selective anti-COVID-19 compound is also, to the best of our knowledge, the first bioactive derivative of favipiravir, the known antiinfluenza and antiviral drug. This new nucleoside analog was designed, synthesized, characterized, computationally studied (through pharmacokinetic calculations along with computational molecular modeling and prediction), and biologically evaluated for its anti-COVID-19 activities (through a validated in vitro anti-COVID-19 assay). The results of the biological assay showed that cyanorona-20 surprisingly exhibited very significant anti-COVID-19 activity (anti-SARS-CoV-2 EC50 = 0.45 µM), and, in addition, it could be also a very promising lead compound for the design of new anti-COVID-19 agents. Cyanorona-20 is a new favipiravir derivative with promise for the treatment of SARS-CoV-2 infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11696-021-01640-9.

10.
Chem Biol Interact ; 343: 109480, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1193249

ABSTRACT

Polyphenolics and 1,3,4-oxadiazoles are two of the most potent bioactive classes of compounds in medicinal chemistry, since both are known for their diverse pharmacological activities in humans. One of their prominent activities is the antimicrobial/antiviral activities, which are much apparent when the key functional structural moieties of both of them meet into the same compounds. The current COVID-19 pandemic motivated us to computationally screen and evaluate our library of previously-synthesized 2-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazoles against the major SARS-CoV-2 protein targets. Interestingly, few ligands showed promising low binding free energies (potent inhibitory interactions/affinities) with the active sites of some coronaviral-2 enzymes, specially the RNA-dependent RNA polymerase (nCoV-RdRp). One of them was 5,5'-{5,5'-[(1R,2R)-1,2-dihydroxyethane-1,2-diyl]bis(1,3,4-oxadiazole-5,2-diyl)}dibenzene-1,2,3-triol (Taroxaz-104), which showed significantly low binding energies (-10.60 and -9.10 kcal/mol) with nCoV-RdRp-RNA and nCoV-RdRp alone, respectively. These binding energies are even considerably lower than those of remdesivir potent active metabolite GS-443902 (which showed -9.20 and -7.90 kcal/mol with the same targets, respectively). Further computational molecular investigation revealed that Taroxaz-104 molecule strongly inhibits one of the potential active sites of nCoV-RdRp (the one with which GS-443902 molecule mainly interacts), since it interacts with at least seven major active amino acid residues of its predicted pocket. The successful repurposing of Taroxaz-104 has been achieved after the promising results of the anti-COVID-19 biological assay were obtained, as the data showed that Taroxaz-104 exhibited very significant anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.42 µM) with interesting effectiveness against the new strains/variants of SARS-CoV-2. Further investigations for the development of Taroxaz-104 and its coming polyphenolic 2,5-disubstituted-1,3,4-oxadiazole derivatives as anti-COVID-19 drugs, through in vivo bioevaluations and clinical trials research, are urgently needed.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Oxadiazoles/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/metabolism , Catalytic Domain , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Drug Repositioning , Enzyme Inhibitors/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Oxadiazoles/metabolism , Protein Binding , SARS-CoV-2/enzymology , Vero Cells
11.
New Journal of Chemistry ; 45(2):761-771, 2021.
Article in English | ProQuest Central | ID: covidwho-1035935

ABSTRACT

Repurposing of known drugs and compounds as anticoronavirus disease 2019 (anti-COVID-19) agents through biological reevaluation of their activities, especially the anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activities, is a new viable trend in drug discovery for the COVID-19 pandemic in 2020. Comprehensive inhibition of the enzymes and proteins of coronavirus and coronavirus 2 (i.e., multitarget inhibition) can be considered one of the most promising strategies for the development of highly potent remedies for COVID-19. However, almost all the reported inhibitors of the different life cycle stages of SARS-CoV-2 lack extreme potency against the major and fateful SARS-CoV-2 enzymes (e.g., RNA-dependent RNA polymerase “RdRp”, papain-like protease “PLpro”, and main protease “Mpro”). Herein, two antioxidant polyphenolic 1,3,4-oxadiazole compounds previously synthesized by me were repurposed and introduced, 1,2,3-tris[5-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazol-2-yl]propan-2-ol (named CoViTris2020) and 5-[5-(7-chloro-4-hydroxyquinolin-3-yl)-1,3,4-oxadiazol-2-yl]benzene-1,2,3-triol (named ChloViD2020), as the first multitarget SARS-CoV-2 inhibitors with higher potencies than other drugs reported to date (about 65, 171, and 303.5 times for CoViTris2020 and 20, 52.5, and 93 times for ChloViD2020 compared to those of remdesivir, ivermectin, and favipiravir, respectively). These two unique 2,5-disubstituted-1,3,4-oxadiazole derivatives were computationally studied (through molecular docking in almost all SARS-CoV-2 proteins and one human protein) and biologically evaluated (through one of the most credible in vitro anti-COVID-19 assays) for their anti-COVID-19 activities. The results of the computational docking showed that CoViTris2020 and ChloViD2020 exhibited very high inhibitory binding affinities with most of the docked SARS-CoV-2/human proteins (e.g., they exhibited low binding energies of −12.00 and −9.60 kcal mol−1, respectively, with RdRp-RNA). Interestingly, the results of the biological assay showed that CoViTris2020 and ChloViD2020 exhibited very high and extremely significant anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.31 and 1.01 μM, respectively). Additionally, they may also be very promising lead compounds for the design and synthesis of new anti-COVID-19 agents (through structural modifications and further computational studies). Therefore, further investigations for the development of CoViTris2020 and ChloViD2020 as anti-COVID-19 drugs through in vivo biological evaluations and clinical trials are necessary. In brief, the development of CoViTris2020 and ChloViD2020 as the first two members of the new and promising class of anti-COVID-19 polyphenolic 2,5-disubstituted-1,3,4-oxadiazole derivatives will result in a therapeutic revolution for the treatment of SARS-CoV-2 infection and its accompanying COVID-19.

12.
Mol Divers ; 25(3): 1839-1854, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1002132

ABSTRACT

Designing anticoronavirus disease 2019 (anti-COVID-19) agents is the primary concern of medicinal chemists/drug designers nowadays. Repurposing of known active compounds against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new effective and time-saving trend in anti-COVID-19 drug discovery. Thorough inhibition of the coronaviral-2 proteins (i.e., multitarget inhibition) is a possible powerful favorable strategy for developing effectively potent drugs for COVID-19. In this new research study, I succeeded to repurpose the two antioxidant polyhydroxy-1,3,4-oxadiazole compounds CoViTris2020 and ChloViD2020 as the first multitarget coronaviral protein blockers with extremely higher potencies (reach about 65 and 304 times, for CoViTris2020, and 20 and 93 times, for ChloViD2020, more potent than remdesivir and favipiravir, respectively). These two 2,5-disubstituted-1,3,4-oxadiazoles were computationally studied (through molecular docking in almost all SARS-CoV-2 proteins) and biologically assessed (through a newly established robust in vitro anti-COVID-19 assay) for their anticoronaviral-2 bioactivities. The data obtained from the docking investigation showed that both ligands promisingly exhibited very strong inhibitory binding affinities with almost all docked enzymes (e.g., they displayed extremely lower binding energies of - 12.00 and - 9.60 kcal/mol, respectively, with the SARS-CoV-2 RNA-dependent RNA polymerase "RdRp"). The results of the biological assay revealed that CoViTris2020 and ChloViD2020 significantly displayed very high anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.31 and 1.01 µM, respectively). Further in vivo/clinical studies for the development of CoViTris2020 and ChloViD2020 as anti-COVID-19 medications are required. In brief, the ascent of CoViTris2020 and ChloViD2020 as the two lead members of the novel family of anti-COVID-19 polyphenolic 2,5-disubstituted-1,3,4-oxadiazole derivatives represents a promising hope in COVID-19 therapy. CoViTris2020 and ChloViD2020 inhibit SARS-CoV-2 life cycle with surprising EC50 values of 0.31 and 1.01 µM, respectively. CoViTris2020 strongly inhibits coronaviral-2 RdRp with exceptionally lower inhibitory binding energy of - 12.00 kcal/mol.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Oxadiazoles/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Oxadiazoles/chemistry , Oxadiazoles/therapeutic use
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