Evaluation of a series of nucleoside analogs as effective anticoronaviral-2 drugs against the Omicron-B.1.1.529/BA.2 subvariant: A repurposing research study.

Mysterious evolution of a new strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant, led to a new challenge in the persistent coronavirus disease 2019 (COVID-19) battle. Objecting the conserved SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) together using one ligand is a successful new tactic to stop SARS-CoV-2 multiplication and COVID-19 progression. The current comprehensive study investigated most nucleoside analogs (NAs) libraries, searching for the most ideal drug candidates expectedly able to act through this double tactic. Gradual computational filtration afforded six different promising NAs, riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir. Further biological assessment proved that riboprine and forodesine are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of about 0.21 and 0.45 µM for riboprine and about 0.23 and 0.70 µM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. These biochemical findings were supported by the prior in silico data. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading. These findings suggest that riboprine and forodesine could serve as prospective lead compounds against COVID-19. Graphical abstract.

A peek behind the curtain in the diagnosis and management of COVID­19­Associated Mucormycosis (CAM).

Coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM) is responsible for a high mortality rate due to its unique and severe host-pathogen interactions. Critically ill or immunocompromised COVID-19 patients are more prone to suffer from aggressive mycoses. Probable victims include those with uncontrolled diabetes mellitus (DM), metabolic acidosis, prolonged neutropenia, increased ferritin levels, hypoxia, and prolonged hospitalization with/without mechanical ventilators and corticosteroids administration. The current review aims to outline the journey of patients with CAM as well as the advantages and disadvantages of the currently available diagnostic techniques. It also discussed the current status of treatment options and caveats in the management of mucormycosis. Multidisciplinary team, early diagnosis, controlling the predisposing condition(s), complete surgical debridement, effective antifungal therapies (e.g., amphotericin B, isavuconazole, and posaconazole), and implementing antifungal stewardship programs are imperative in CAM cases.

Retraction Note to: Discovery of (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20): the first potent and specific anti-COVID-19 drug.

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

CoViTris2020 and ChloViD2020: a striking new hope in COVID-19 therapy.

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.

Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain.

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.

RETRACTED ARTICLE: Discovery of (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20): the first potent and specific anti-COVID-19 drug.

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.

RNA: The most attractive target in recent viral diseases.

As an expert in the field of drug design and discovery, I tried, in this up-to-date perspective or commentary article, to recap and shed light on the previous and latest revolutionary strategies employed in medicinal and therapeutic chemistry to target the principal viral weapon used by virulent RNA viruses (e.g., the severe acute respiratory syndrome coronavirus 2 "SARS-CoV-2") to infect humans and spread infections, the genomic RNA strands. These strategies act by taking advantage of the weakness points of this attractive bioweapon to disable or attack it (itself), accordingly stop the entire viral reproduction, and effectively end the severe microbial infections such as the coronavirus disease 2019 (COVID-19). The generation of respective slightly falsely-weaved RNA strands, either endogenously or exogenously, is the principal key for designing most of these therapeutic approaches.

Revolutionizing Playing with Skeleton Atoms: Molecular Editing Surgery in Medicinal Chemistry

Finding the most perfect drug candidates in the fields of drug discovery and medicinal chemistry will remain the main interest of drug designers. This concern necessitates organic and medicinal chemists, in most examples, to precisely design and search for drug candidates that are very analogous to the present effective drugs with solving, mainly, their proven critical pharmacological and clinical issues through slightly changing one or two atoms of the principal functional skeletons of the molecules of these present therapeutics by atom swapping, removal, and/or addition procedures in organic chemical synthesis. This accurate modern chemicosimilarity tactic in drug discovery surely saves time while keeping us very close, or sometimes highly superior, to the parent pharmacophoric bioactivity (i.e., keeping considerable analogy to the parent therapeutic molecule). From this perspective and logic, the science of skeletal editing of molecules (i.e., skeletal molecular editing) arose in the era of artificial intelligence (AI) and its dramatic predictions. As a pioneer in this modern branch in pharmaceutical and therapeutic organic chemistry, in this up-to-date minireview and perspective article, an attempt was made to introduce skeletal editing and its synthetic surgeries (over molecules) to the audience (including irrelevant readers) in a simpler and more attractive way as a novel chemical technology, highlighting the previous synthetic trials (in general), demonstrating the three main techniques, and, finally, discussing the future therapeutic needs and scenarios from a medicinal chemist's viewpoint.

The role of Aedes aegypti in inducing/aggravating IgE-mediated allergic airway disease: extensive computational studies for identification of allergenic proteins.

Respiratory allergies have become a major public health concern and affect one-third of the world's population. Several factors like environmental changes, industrialization, and immunologic interactions are reported to contribute to allergic respiratory diseases. Immunological reactions because of mosquito bite (allergic proteins) have been reported to have a high contribution to IgE-mediated allergic airway disease but they are largely ignored. In this study, we aim to predict the potential allergens (proteins) from Aedes aegypti that might play a role in the reactions of IgE-mediated allergic airway diseases. The allergens are identified from an extensive literature search and the 3D structures were prepared using the SwissDock server. Computational studies were performed to identify the potential allergens that might be responsible for IgE-mediated allergies. Our docking and molecular dynamics (MD) simulation results suggest that ADE-3, an allergen from Aedes aegypti, has the highest docking score and is predicted to be responsible for IgE-mediated allergic reaction(s). Overall, this study highlights the importance of immunoinformatics, and the obtained information can be used for designing prophylactic peptide vaccine candidates and inhibitors for controlling IgE-mediated inflammations.Communicated by Ramaswamy H. Sarma.

Potent Dual Polymerase/Exonuclease Inhibitory Activities of Antioxidant Aminothiadiazoles Against the COVID-19 Omicron Virus: A Promising In Silico/In Vitro Repositioning Research Study.

Recently, natural and synthetic nitrogenous heterocyclic antivirals topped the scene as first choices for the treatment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their accompanying disease, the coronavirus disease 2019 (COVID-19). Meanwhile, the mysterious evolution of a new strain of SARS-CoV-2, the Omicron variant and its sublineages, caused a new defiance in the continual COVID-19 battle. Hitting the two principal coronaviral-2 multiplication enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) synchronously using the same ligand is a highly effective novel dual pathway to hinder SARS-CoV-2 reproduction and stop COVID-19 progression irrespective of the SARS-CoV-2 variant type since RdRps and ExoNs are widely conserved among all SARS-CoV-2 strains. Herein, the present computational/biological study screened our previous small libraries of nitrogenous heterocyclic compounds, searching for the most ideal drug candidates predictably able to efficiently act through this double approach. Theoretical filtration gave rise to three promising antioxidant nitrogenous heterocyclic compounds of the 1,3,4-thiadiazole type, which are CoViTris2022, Taroxaz-26, and ChloViD2022. Further experimental evaluation proved for the first time, utilizing the in vitro anti-RdRp/ExoN and anti-SARS-CoV-2 bioassays, that ChloViD2022, CoViTris2022, and Taroxaz-26 could effectively inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of 0.17 and 0.41 µM for ChloViD2022, 0.21 and 0.69 µM for CoViTris2022, and 0.23 and 0.73 µM for Taroxaz-26, respectively, transcending the anti-COVID-19 drug molnupiravir. The preliminary in silico outcomes greatly supported these biochemical results, proposing that the three molecules potently strike the key catalytic pockets of the SARS-CoV-2 (Omicron variant) RdRp's and ExoN's vital active sites. Moreover, the idealistic pharmacophoric hallmarks of CoViTris2022, Taroxaz-26, and ChloViD2022 molecules relatively make them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading, with their highly flexible structures open for various kinds of chemical derivatization. To cut it short, the present pivotal findings of this comprehensive work disclosed the promising repositioning potentials of the three 2-aminothiadiazoles, CoViTris2022, Taroxaz-26, and ChloViD2022, to successfully interfere with the crucial biological interactions of the coronaviral-2 polymerase/exoribonuclease with the four principal RNA nucleotides, and, as a result, cure COVID-19 infection, encouraging us to rapidly start the three drugs' broad preclinical/clinical anti-COVID-19 evaluations. Dual SARS-CoV-2 polymerase (RdRp) and exoribonuclease (ExoN) inhibition via nucleoside mimicry is a very effective novel approach for COVID-19 infection therapy. Hydroxylated nitrogenous heterocyclic compounds are currently considered first choices in COVID-19 therapy. Extensive computational investigations disclosed three synthetic 5-substituted-2-amino-1,3,4-thiadiazoles, CoViTris2022, Taroxaz-26, and ChloViD2022, with ideal anti-RdRp/ExoN features. ChloViD2022 was ranked the top among the three NAs, with biochemical anti-RdRp EC50 value of 0.17 µM. ChloViD2022 accordingly displayed excellent anti-SARS-CoV-2 EC50 value of 0.41 µM against the Omicron variant.

Strong Dual Antipolymerase/Antiexonuclease Actions of Some Aminothiadiazole Antioxidants: A Promising In-Silico/In-Vitro Repurposing Research Study against the COVID-19 Omicron Virus (B.1.1.529.3 Lineage).

Currently, nitrogen-containing heterocyclic virucides take the lead as top options for treating the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their escorting disease, the coronavirus disease 2019 (COVID-19). But unfortunately, the sudden emergence of a new strain of SARS-CoV-2, the Omicron variant and its lineages, complicated matters in the incessant COVID-19 battle. Goaling the two paramount coronaviral-2 multiplication enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) at synchronous times using single ligand is a quite effective new binary avenue to restrain SARS-CoV-2 reproduction and cease COVID-19 progression irrespective of the SARS-CoV-2 strain type, as RdRps and ExoNs are vastly conserved in all SARS-CoV-2 strains. The presented in-silico/in-vitro research winnowed our own small libraries of antioxidant nitrogenous heterocyclic compounds, inspecting for the utmost convenient drug candidates expectedly capable of effectively working through this dual tactic. Computational screening afforded three promising compounds of the antioxidant 1,3,4-thiadiazole class, which were named ChloViD2022, Taroxaz-26, and CoViTris2022. Subsequent biological examination, employing the in-vitro anti-RdRp/anti-ExoN and anti-SARS-CoV-2 assays, exclusively demonstrated that ChloViD2022, CoViTris2022, and Taroxaz-26 could efficiently block the replication of the new lineages of SARS-CoV-2 with considerably minute anti-RdRp and anti-SARS-CoV-2 EC50 values of about 0.18 and 0.44 µM for ChloViD2022, 0.22 and 0.72 µM for CoViTris2022, and 0.25 and 0.78 µM for Taroxaz-26, in the order, overtaking the standard anti-SARS-CoV-2 drug molnupiravir. These biochemical findings were optimally presupported by the results of the prior in-silico screening, suggesting that the three compounds might potently hit the catalytic active sites of the virus's RdRp and ExoN enzymes. Furthermore, the perfect pharmacophoric features of ChloViD2022, Taroxaz-26, and CoViTris2022 molecules make them typical dual inhibitors of SARS-CoV-2 replication and proofreading, with their relatively flexible structures eligible for diverse forms of chemical modification. In sum, the current important results of this thorough research work exposed the interesting repurposing potential of the three 2-amino-1,3,4-thiadiazole ligands, ChloViD2022, Taroxaz-26, and CoViTris2022, to effectively conflict with the vital biointeractions between the coronavirus's polymerase/exoribonuclease and the four essential RNA nucleotides, and, accordingly, arrest COVID-19 disease, persuading the relevant investigators to quickly begin the three agents' comprehensive preclinical and clinical anti-COVID-19 assessments.

Dual computational and biological assessment of some promising nucleoside analogs against the COVID-19-Omicron variant.

Nucleoside analogs/derivatives (NAs/NDs) with potent antiviral activities are now deemed very convenient choices for the treatment of coronavirus disease 2019 (COVID-19) arisen by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. At the same time, the appearance of a new strain of SARS-CoV-2, the Omicron variant, necessitates multiplied efforts in fighting COVID-19. Counteracting the crucial SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) jointly altogether using the same inhibitor is a quite successful new plan to demultiplicate SARS-CoV-2 particles and eliminate COVID-19 whatever the SARS-CoV-2 subtype is (due to the significant conservation nature of RdRps and ExoNs in the different SARS-CoV-2 strains). Successive in silico screening of known NAs finally disclosed six different promising NAs, which are riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir, respectively, that predictably can act through the planned dual-action mode. Further in vitro evaluations affirmed the anti-SARS-CoV-2/anti-COVID-19 potentials of these NAs, with riboprine and forodesine being at the top. The two NAs are able to effectively antagonize the replication of the new virulent SARS-CoV-2 strains with considerably minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of 189 and 408 nM for riboprine and 207 and 657 nM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. Furthermore, the favorable structural characteristics of the two molecules qualify them for varied types of isosteric and analogistic chemical derivatization. In one word, the present important outcomes of this comprehensive dual study revealed the anticipating repurposing potentials of some known nucleosides, led by the two NAs riboprine and forodesine, to successfully discontinue the coronaviral-2 polymerase/exoribonuclease interactions with RNA nucleotides in the SARS-CoV-2 Omicron variant (BA.5 sublineage) and accordingly alleviate COVID-19 infections, motivating us to initiate the two drugs' diverse anti-COVID-19 pharmacological evaluations to add both of them betimes in the COVID-19 therapeutic protocols.

Promising Experimental Anti-SARS-CoV-2 Agent "SLL-0197800": The Prospective Universal Inhibitory Properties against the Coming Versions of the Coronavirus.

Isoquinoline derivatives having some nucleosidic structural features are considered as candidate choices for effective remediation of the different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their following disease, the coronavirus disease 2019 (COVID-19). SLL-0197800 is a recently discovered isoquinoline compound with potential strong universal anticoronaviral activities against SARS-CoV-2 and its previous strains. SLL-0197800 nonspecifically hits the main protease (Mpro) enzyme of the different coronaviruses. Herein in the present study, we tested the probability of the previous findings of this experimental agent to be extended to comprise any coronavirus through concurrently disrupting the mutable-less replication enzymes like the RNA-dependent RNA polymerase (RdRp) protein as well as the 3'-to-5' exoribonuclease (ExoN) protein. The in vitro anti-RdRp/ExoN assay revealed the potent inhibitory activities of SLL-0197800 on the coronaviral replication with minute values of anti-RdRp and anti-RdRp/ExoN EC50 (about 0.16 and 0.27 µM, respectively). The preliminary in silico outcomes significantly supported these biochemical findings. To put it simply, the present important results of these extension efforts greatly reinforce and extend the SLL-0197800's preceding findings, showing that the restraining/blocking actions (i.e., inhibitory activities) of this novel investigational anti-SARS-CoV-2 agent against the Mpro protein could be significantly extended against other copying and multiplication enzymes such as RdRp and ExoN, highlighting the potential use of SLL-0197800 against the coming versions of the homicidal coronavirus (if any), i.e., revealing the probable nonspecific anticoronaviral features and qualities of this golden experimental drug against nearly any coronaviral strain, for instance, SARS-CoV-3.

Novel Investigational Anti-SARS-CoV-2 Agent Ensitrelvir "S-217622": A Very Promising Potential Universal Broad-Spectrum Antiviral at the Therapeutic Frontline of Coronavirus Species.

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.

Discovery of 1-(5-bromopyrazin-2-yl)-1-[3-(trifluoromethyl)benzyl]urea as a promising anticancer drug via synthesis, characterization, biological screening, and computational studies.

Cancer and different types of tumors are still the most resistant diseases to available therapeutic agents. Finding a highly effective anticancer drug is the first target and concern of thousands of drug designers. In our attempts to address this concern, a new pyrazine derivative, 1-(5-bromopyrazin-2-yl)-1-[3-(trifluoromethyl)benzyl]urea (BPU), was designed via structural optimization and synthesized to investigate its anticancer/antitumor potential. The in-vitro anticancer properties of BPU were evaluated by MTT assay using selected cell lines, including the Jurkat, HeLa, and MCF-7 cells. The Jurkat cells were chosen to study the effect of BPU on cell cycle analysis using flow cytometry technique. BPU exhibited an effective cytotoxic ability in all the three cell lines assessed. It was found to be more prominent with the Jurkat cell line (IC50 = 4.64 ± 0.08 µM). When it was subjected to cell cycle analysis, this compound effectively arrested cell cycle progression in the sub-G1 phase. Upon evaluating the antiangiogenic potential of BPU via the in-vivo/ex-vivo shell-less chick chorioallantoic membrane (CAM) assays, the compound demonstrated very significant findings, revealing a complementary supportive action for the compound to act as a potent anticancer agent through inhibiting blood vessel formation in tumor tissues. Moreover, the docking energy of BPU computationally scored - 9.0 kcal/mol with the human matrix metalloproteinase 2 (MMP-2) and - 7.8 kcal/mol with the human matrix metalloproteinase 9 (MMP-9), denoting promising binding results as compared to the existing drugs for cancer therapy. The molecular dynamics (MD) simulation outcomes showed that BPU could effectively bind to the previously-proposed catalytic sites of both MMP-2 and MMP-9 enzymes with relatively stable statuses and good inhibitory binding abilities and parameters. Our findings suggest that the compound BPU could be a promising anticancer agent since it effectively inhibited cell proliferation and can be selected for further in-vitro and in-vivo investigations. In addition, the current results can be extensively validated by conducting wet-lab analysis so as to develop novel and better derivatives of BPU for cancer therapy with much less side effects and higher activities.

Potent Inhibitory Activities of the Adenosine Analogue Cordycepin on SARS-CoV-2 Replication.

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.

Efficacious Preclinical Repurposing of the Nucleoside Analogue Didanosine against COVID-19 Polymerase and Exonuclease.

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.

Forodesine and Riboprine Exhibit Strong Anti-SARS-CoV-2 Repurposing Potential: In Silico and In Vitro Studies.

Lately, nucleos(t)ide antivirals topped the scene as top options for the treatment of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Targeting the two broadly conserved SARS-CoV-2 enzymes, RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN), together using only one shot is a very successful new tactic to stop SARS-CoV-2 multiplication irrespective of the SARS-CoV-2 variant type. Herein, the current studies investigated most nucleoside analogue (NA) libraries, searching for the ideal drug candidates expectedly able to act through this double tactic. Gradual computational filtration gave rise to six different promising NAs along with their corresponding triphosphate (TP) nucleotides. The subsequent biological assessment proved for the first time that, among the six NAs, riboprine and forodesine are able to hyperpotently inhibit the replication of the Omicron strain of SARS-CoV-2 with extremely low in vitro anti-RdRp, anti-ExoN, and anti-SARS-CoV-2 EC50 values of about 0.18, 0.28, and 0.40 µM for riboprine and about 0.20, 0.31, and 0.65 µM for forodesine, respectively, surpassing remdesivir and molnupiravir. The significant probability that both compounds may also act as prodrugs for their final TP nucleotides in vivo pushed us to examine the same activities for forodesine-TP and riboprine-TP. Both nucleotides similarly displayed very promising results, respectively, which are much better than those for the two reference TP nucleotides, GS-443902 and ß-d-N4-hydroxycytidine 5'-TP (NHC-TP). The prior in silico data supported these biochemical findings, suggesting that riboprine and forodesine molecules and their expected active TP metabolites strongly hit the key catalytic pockets of the SARS-CoV-2 RdRp's and ExoN's main active sites. In brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two bioactive nucleosides forodesine and riboprine and their TP nucleotides to effectively shut down the polymerase/exoribonuclease-RNA nucleotide interactions of SARS-CoV-2 and consequently treat COVID-19 infections.

A Series of Adenosine Analogs as the First Efficacious Anti-SARS-CoV-2 Drugs against the B.1.1.529.4 Lineage: A Preclinical Repurposing Research Study.

Given the rapid progression of the coronavirus disease 2019 (COVID-19) pandemic, an ultrafast response was urgently required to handle this major public crisis. To contain the pandemic, investments are required to develop diagnostic tests, prophylactic vaccines, and novel therapies. Lately, nucleoside analog (NA) antivirals topped the scene as top options for the treatment of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Meanwhile, the continuous generation of new lineages of the SARS-CoV-2 Omicron variant caused a new challenge in the persistent COVID-19 battle. Hitting the two crucial SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) collectively together using only one single ligand is a very successful new approach to stop SARS-CoV-2 multiplication and combat COVID-19 irrespective of the SARS-CoV-2 variant type because RdRps and ExoNs are broadly conserved among all SARS-CoV-2 strains. Herein, the current comprehensive study investigated most NAs libraries, searching for the most ideal drug candidates expectedly able to perfectly act through this double tactic. Gradual computational filtration gave rise to six different promising NAs, which are riboprine, forodesine, tecadenoson, nelarabine, vidarabine, and maribavir, respectively. Further biological assessment proved for the first time, using the in vitro anti-RdRp/ExoN and anti-SARS-CoV-2 bioassays, that riboprine and forodesine, among all the six tested NAs, are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of about 0.22 and 0.49 µM for riboprine and about 0.25 and 0.73 µM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. The prior in silico data supported these biochemical findings, suggesting that riboprine and forodesine molecules strongly hit the key catalytic pockets of the SARS-CoV-2 (Omicron variant) RdRp's and ExoN's main active sites. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading, with their relatively flexible structures open for diverse types of chemical derivatization. In Brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two nucleosides riboprine and forodesine to effectively shut down the polymerase/exoribonuclease-RNA nucleotides interactions of the SARS-CoV-2 Omicron variant and consequently treat COVID-19 infections, motivating us to rapidly begin the two drugs' broad preclinical/clinical anti-COVID-19 bioevaluations, hoping to combine both drugs soon in the COVID-19 treatment protocols.