Therapeutic potential of salicylamide derivatives for combating viral infections.

Since time immemorial human beings have constantly been fighting against viral infections. The ongoing and devastating coronavirus disease 2019 pandemic represents one of the most severe and most significant public health emergencies in human history, highlighting an urgent need to develop broad-spectrum antiviral agents. Salicylamide (2-hydroxybenzamide) derivatives, represented by niclosamide and nitazoxanide, inhibit the replication of a broad range of RNA and DNA viruses such as flavivirus, influenza A virus, and coronavirus. Moreover, nitazoxanide was effective in clinical trials against different viral infections including diarrhea caused by rotavirus and norovirus, uncomplicated influenza A and B, hepatitis B, and hepatitis C. In this review, we summarize the broad antiviral activities of salicylamide derivatives, the clinical progress, and the potential targets or mechanisms against different viral infections and highlight their therapeutic potential in combating the circulating and emerging viral infections in the future.

Anti-viral activity of thiazole derivatives: an updated patent review.

INTRODUCTION: Several viral infections cause life-threatening consequences in humans, making them the most serious public health concerns. Despite the fact that several antiviral medicines are available on the market, there is no full treatment for many important viral infections. To date, antiviral medicines have significantly reduced the spread of epidemics, but their continued use has resulted in the creation of drug-resistant variants throughout time. As a result, the development of new, safe, and efficient antiviral drugs is critical. AREAS COVERED: This review covered reports in the patent literature in the period 2014 to the first quarter of 2021 on the antiviral activities of thiazole derivatives. These molecules were reported to inhibit a wide range of viruses including influenza viruses, coronaviruses, herpes viruses, hepatitis B and C, bovine viral diarrhea virus, chikungunya virus and human immunodeficiency viruses. EXPERT OPINION: The most bioactive molecules can be used as lead structures for the development of new thiazole compounds with potent and selective antiviral activity. In addition, more efforts are needed to better understand the host-virus interactions for the discovery and development of new therapeutic agents and creative treatment strategies that are supposed to improve rates of clinical cure of the serious viruses.

Synthesis and Antiviral Properties of Camphor-Derived Iminothiazolidine-4-Ones and 2,3-Dihydrothiazoles.

A set of heterocyclic products was synthesized from natural (+)-camphor and semi-synthetic (-)-camphor. Then, 2-Imino-4-thiazolidinones and 2,3-dihydrothiazoles were obtained using a three-step procedure. For the synthesized compounds, their antiviral activity against the vaccinia virus and Marburg virus was studied. New promising agents active against both viruses were found among the tested compounds.

Synthesis and Biochemical Evaluation of 8H-Indeno[1,2-d]thiazole Derivatives as Novel SARS-CoV-2 3CL Protease Inhibitors.

The COVID-19 pandemic caused by SARS-CoV-2 is a global burden on human health and economy. The 3-Chymotrypsin-like cysteine protease (3CLpro) becomes an attractive target for SARS-CoV-2 due to its important role in viral replication. We synthesized a series of 8H-indeno[1,2-d]thiazole derivatives and evaluated their biochemical activities against SARS-CoV-2 3CLpro. Among them, the representative compound 7a displayed inhibitory activity with an IC50 of 1.28 ± 0.17 µM against SARS-CoV-2 3CLpro. Molecular docking of 7a against 3CLpro was performed and the binding mode was rationalized. These preliminary results provide a unique prototype for the development of novel inhibitors against SARS-CoV-2 3CLpro.

Synthesis, in vitro bioassays, and computational study of heteroaryl nitazoxanide analogs.

Antiprotozoal drug nitazoxanide (NTZ) has shown diverse pharmacological properties and has appeared in several clinical trials. Herein we present the synthesis, characterization, in vitro biological investigation, and in silico study of four hetero aryl amide analogs of NTZ. Among the synthesized molecules, compound 2 and compound 4 exhibited promising antibacterial activity against Escherichia coli (E. coli), superior to that displayed by the parent drug nitazoxanide as revealed from the in vitro antibacterial assay. Compound 2 displayed zone of inhibition of 20 mm, twice as large as the parent drug NTZ (10 mm) in their least concentration (12.5 µg/ml). Compound 1 also showed antibacterial effect similar to that of nitazoxanide. The analogs were also tested for in vitro cytotoxic activity by employing cell counting kit-8 (CCK-8) assay technique in HeLa cell line, and compound 2 was identified as a potential anticancer agent having IC50 value of 172 µg which proves it to be more potent than nitazoxanide (IC50  = 428 µg). Furthermore, the compounds were subjected to molecular docking study against various bacterial and cancer signaling proteins. The in vitro test results corroborated with the in silico docking study as compound 2 and compound 4 had comparatively stronger binding affinity against the proteins and showed a higher docking score than nitazoxanide toward human mitogen-activated protein kinase (MAPK9) and fatty acid biosynthesis enzyme (FabH) of E. coli. Moreover, the docking study demonstrated dihydrofolate reductase (DHFR) and thymidylate synthase (TS) as probable new targets for nitazoxanide and its synthetic analogs. Overall, the study suggests that nitazoxanide and its analogs can be a potential lead compound in the drug development.

Thiazole-based SARS-CoV-2 protease (COV Mpro ) inhibitors: Design, synthesis, enzyme inhibition, and molecular modeling simulations.

As an attempt to contribute to the efforts of combating the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for COVID-19, new analogs of the repurposed drug nitazoxanide which showed promising inhibitory efficacy on a viral protease enzyme were designed, synthesized and evaluated for their inhibitory activity on the main protease of the SARS-CoV-2 virus, using the COV2-3CL protease inhibition assay. The obtained results showed that the N-(substituted-thiazol-2-yl)cinnamamide analogs 19, 20, and 21 were the most active compounds with IC50 values of 22.61, 14.7, 21.99 µM, respectively, against the viral protease compared to the reference drugs, nitazoxanide, and lopinavir. Molecular modeling studies showed binding interactions of 19, 20, and 21 with hydrogen bonds to Gln189 and Glu166, arene-arene interaction between the thiazole moiety and His41, and other hydrophobic interactions between the ethene spacer moiety and Asn142. Moreover, an extra arene-arene interaction between substituted benzo[d]thiazole and His41 was observed regarding compounds 19 and 21. Surface mapping and flexible alignment proved the structural similarity between the new drug candidates and nitazoxanide. Compliance of the new compounds to Lipinski's rule of five was investigated and absorption, distribution, metabolism, excretion, and toxicology data were predicted. The newly synthesized compounds are promising template ligands for further development and optimization.

Discovery of highly potent SARS-CoV-2 Mpro inhibitors based on benzoisothiazolone scaffold.

The COVID-19 pandemic has drastically impacted global economies and public health. Although vaccine development has been successful, it was not sufficient against more infectious mutant strains including the Delta variant indicating a need for alternative treatment strategies such as small molecular compound development. In this work, a series of SARS-CoV-2 main protease (Mpro) inhibitors were designed and tested based on the active compound from high-throughput diverse compound library screens. The most efficacious compound (16b-3) displayed potent SARS-CoV-2 Mpro inhibition with an IC50 value of 116 nM and selectivity against SARS-CoV-2 Mpro when compared to PLpro and RdRp. This new class of compounds could be used as potential leads for further optimization in anti COVID-19 drug discovery.

Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence.

SARS-CoV-2, the causative agent of COVID-19, has caused an unprecedented global health crisis. The SARS-CoV-2 spike, a surface-anchored trimeric class-I fusion glycoprotein essential for viral entry, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of SARS-CoV-2 spike variants that facilitate virus spread and may affect vaccine efficacy highlights the need to identify novel antiviral strategies for COVID-19 therapy. Here, we demonstrate that nitazoxanide, an antiprotozoal agent with recognized broad-spectrum antiviral activity, interferes with SARS-CoV-2 spike maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Engineering multiple SARS-CoV-2 variant-pseudoviruses and utilizing quantitative cell-cell fusion assays, we show that nitazoxanide-induced spike modifications hinder progeny virion infectivity as well as spike-driven pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. Nitazoxanide, being equally effective against the ancestral SARS-CoV-2 Wuhan-spike and different emerging variants, including the Delta variant of concern, may represent a useful tool in the fight against COVID-19 infections.

The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation.

Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.

Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective.

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.

Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.

There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro. Mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation. Masitinib was also effective in vitro against all tested variants of concern (B.1.1.7, B.1.351, and P.1).

Development of a High-Throughput Screening Assay to Identify Inhibitors of the SARS-CoV-2 Guanine-N7-Methyltransferase Using RapidFire Mass Spectrometry.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a significant threat to human health. Despite its similarity to related coronaviruses, there are currently no specific treatments for COVID-19 infection, and therefore there is an urgent need to develop therapies for this and future coronavirus outbreaks. Formation of the cap at the 5' end of viral RNA has been shown to help coronaviruses evade host defenses. Nonstructural protein 14 (nsp14) is responsible for N7-methylation of the cap guanosine in coronaviruses. This enzyme is highly conserved among coronaviruses and is a bifunctional protein with both N7-methyltransferase and 3'-5' exonuclease activities that distinguish nsp14 from its human equivalent. Mutational analysis of SARS-CoV nsp14 highlighted its role in viral replication and translation efficiency of the viral genome. In this paper, we describe the characterization and development of a high-throughput assay for nsp14 utilizing RapidFire technology. The assay has been used to screen a library of 1771 Food and Drug Administration (FDA)-approved drugs. From this, we have validated nitazoxanide as a selective inhibitor of the methyltransferase activity of nsp14. Although modestly active, this compound could serve as a starting point for further optimization.

Inflammation control and improvement of cognitive function in COVID-19 infections: is there a role for kynurenine 3-monooxygenase inhibition?

The novel respiratory virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), emerged during late 2019 and spread rapidly across the world. It is now recognised that the nervous system can be affected in COVID-19, with several studies reporting long-term cognitive problems in patients. The metabolic pathway of tryptophan degradation, known as the kynurenine pathway (KP), is significantly activated in patients with COVID-19. KP metabolites have roles in regulating both inflammatory/immune responses and neurological functions. In this review, we speculate on the effects of KP activation in patients with COVID-19, and how modulation of this pathway might impact inflammation and reduce neurological symptoms.

A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19.

The global pandemic of Coronavirus Disease 2019 (COVID-19) has brought the world to a grinding halt. A major cause of concern is the respiratory distress associated mortality attributed to the cytokine storm. Despite myriad rapidly approved clinical trials with repurposed drugs, and time needed to develop a vaccine, accelerated search for repurposed therapeutics is still ongoing. In this review, we present Nitazoxanide a US-FDA approved antiprotozoal drug, as one such promising candidate. Nitazoxanide which is reported to exert broad-spectrum antiviral activity against various viral infections, revealed good in vitro activity against SARS-CoV-2 in cell culture assays, suggesting potential for repurposing in COVID-19. Furthermore, nitazoxanide displays the potential to boost host innate immune responses and thereby tackle the life-threatening cytokine storm. Possibilities of improving lung, as well as multiple organ damage and providing value addition to COVID-19 patients with comorbidities, are other important facets of the drug. The review juxtaposes the role of nitazoxanide in fighting COVID-19 pathogenesis at multiple levels highlighting the great promise the drug exhibits. The in silico data and in vitro efficacy in cell lines confirms the promise of nitazoxanide. Several approved clinical trials world over further substantiate leveraging nitazoxanide for COVID-19 therapy.

Antiviral treatment in COVID-19: which is the most promising?-a narrative review.

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.

Thiazole Compounds as Antiviral Agents: An Update.

BACKGROUND: Thiazole is a good nucleus owing to its various pharmaceutical applications. Thiazole containing compounds (thiazoles) have shown various biological activities like antioxidant, analgesic, antibacterial, anticancer, antiallergic, antihypertensive, antiinflammatory, antimalarial, antifungal and antipsychotic. The scaffold is present in more than 18 FDA approved drugs and also in more than 70 experimental drugs. Only a few reviews are available in the literature despite its great medicinal importance. During the course of time, this scaffold has been studied extensively for its antiviral activities and provided compounds with activity in the nM range. However, no focused review is available on the compilation of antiviral activities shown by this scaffold. OBJECTIVE: In the present review, we have made an effort to compile antiviral literature of thiazoles reported from the year 2011 to till date. METHODS: We searched the SciFinder database (excluding patent literature) with keywords like "antiviral", "anti-HIV" and "virus". Further filters were applied for the year of publication and keywords thiazole, reviews etc. to find relevant literature reported on the antiviral activities of thiazoles. RESULTS: Nearly, 50 research articles were selected to compile and review the antiviral literature of thiazoles reported from the year 2011 to till date. Compounds 8, 25, 40, 62, 72, 73, 91, 112, 113, 131, 137, 175, 198, 200, 201 and 213 were reported in the literature with potent antiviral activity against CVB, SARS, RSV, HCV, HRV, VZV, TMV, FMDV, DENV, YFV, influenza virus, Junin virus, HIV-1, HSV, VV and EBV, respectively. CONCLUSION: There is further scope for the synthesis and evaluation of novel thiazole compounds by taking the most active compounds as lead structures. In conclusion, this review provides an overview of antiviral activities of thiazole compounds reported from the year 2011 to till date.

Quantitative proteomic analysis of the tizoxanide effect in vero cells.

Nitazoxanide (NTZ) is effective against helminths and numerous microorganisms, including bacteria and viruses. In vivo, NTZ is metabolized into Tizoxanide (TIZ), which is the active circulating metabolite. With the emergence of SARS-Cov-2 as a Pandemic agent, NTZ became one of the molecules already approved for human use to engage clinical trials, due to results in vitro showing that NTZ was highly effective against the SARS-Cov-2, agent of COVID-19. There are currently several ongoing clinical trials mainly in the USA and Brazil involving NTZ due not only to the in vitro results, but also for its long-known safety. Here, we study the response of Vero cells to TIZ treatment and unveil possible mechanisms for its antimicrobial effect, using a label-free proteomic approach (LC/MS/MS) analysis to compare the proteomic profile between untreated- and TIZ-treated cells. Fifteen differentially expressed proteins were observed related to various biological processes, including translation, intracellular trafficking, RNA processing and modification, and signal transduction. The broad antimicrobial range of TIZ points towards its overall effect in lowering cell metabolism and RNA processing and modification. The decreased levels of FASN, HNRNPH and HNRNPK with the treatment appear to be important for antiviral activity.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2.

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Mysterious Virus: A Review on Behavior and Treatment Approaches of the Novel Coronavirus, 2019-nCoV.

At the end of the year 2019, the novel coronavirus (2019-nCoV) was spreading in Wuhan, China, and the outbreak process has a high speed. It was recognized as a pandemic by the World Health Organization (WHO) on 11 March 2020. Coronaviruses are enveloped and single-stranded RNA that have several families including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The pathogenesis mechanism and disease outcomes of SARS and MERS are now clear to some extent, but little information is available for 2019-nCoV. This newly identified corona virus infection represents flu-like symptoms, but usually the first symptoms are fever and dry cough. There has been no specific treatment against 2019-nCoV up to now, and physicians only apply supportive therapy. In the present article, we made an attempt to review the behavior of the virus around the world, epidemiology, a pathway for influx into the host cells, clinical presentation, as well as the treatments currently in use and future approaches; nitazoxanide may be our dream drug. We hope that this review has a positive impact on public knowledge for helping to deal with the 2019-nCoV and move one step forward toward its treatment in the near future.