Antiviral Activity of Pyrimidine Containing Compounds: Patent Review.

Viruses are still the most prevalent infectious pathogens on a worldwide scale, with many of them causing life-threatening illnesses in humans. Influenza viruses, because of their significant morbidity and mortality, continue to pose a major threat to human health. According to WHO statistics, seasonal influenza virus epidemics are predicted to cause over 2 million severe illness cases with high death rates yearly. The whole world has been suffering from the COVID-19 epidemic for two years and is still suffering so far, and the deaths from this virus have exceeded three million cases. Because the great majority of viral infections do not have a specific medication or vaccination, discovering novel medicines remains a vital task. This review covers reports in the patent literature from 1980 to the end of 2021 on the antiviral activities of pyrimidine moieties. The patent database, SciFinder, was used to locate patent applications. A large variety of pyrimidine molecules have been produced and tested for antiviral activity over the last decade. These molecules were reported to inhibit a wide range of viruses, including influenza virus, respiratory syncytial virus, rhinovirus, dengue virus, herpes virus, hepatitis B and C, and human immunodeficiency virus. The cytotoxicity of the developed pyrimidine derivatives was tested in almost all reported studies and the selectivity index was calculated to show the selectivity and safety of such molecules. From the remarkable activity of pyrimidine compounds as antivirals for several dangerous viruses, we expect that these derivatives will be used as potent drugs in the very near future.

Synthesis, Docking Study of Some Novel Chromeno[4',3'-B]Pyrano[6,5-D]Pyrimidine Derivatives Against Covid-19 Main Protease (MPRO) (6LU7, 6M03).

AIMS: In this work, some new chromeno[4',3'-b]pyrano[6,5-d]pyrimidines,3-amino and 3-methyl-5-aryl-4-imino-5(H)-chromeno[4',3'-b]pyrano[6,5-d]pyrimidine-6-ones derivatives were synthesized. BACKGROUND: Chromenopyrimidines have attracted significant attention recently because of their activities, such as antiviral and cytotoxic activity. OBJECTIVE: All synthesized compounds were characterized using IR, 1H-NMR, Mass Spectroscopy, and elemental analysis data. METHOD: Molecular docking studies were carried out to determine the inhibitory action of studied ligands against the Main Protease (6LU7, 6m03) of coronavirus (COVID-19). Moreover, the Lipinski Rule parameters were calculated for the synthesized compounds. RESULT: The result of the docking studies showed a significant inhibitory action against the Main protease (Mpro) of SARS-CoV-2, and the binding energy (ΔG) values of the ligands against the protein (6LU7, 6M03) are -7.8 to -9.9 Kcal/mole. CONCLUSION: It may conclude that some ligands were likely to be considered lead-like against the main protease of SARS-CoV-2.

Synthesis and Antiviral Efficacy of Pyrimidine Analogs Targeting Viral Pathways

To date, viruses are known to cause chronic to acute pathogenesis. Nevertheless, antiviral drugs have been known for their medicinal applications for the last few decades to treat infections caused by these pathogens. Despite advancements in the field of vaccination and antiviral drugs, there is a need for a molecule that can eradicate or control viral infection without getting resistance from pathogens will be a real challenge. This review covers possible ways to treat viral infections with pyrimidine and its mimics compared to known antiviral drugs. A comprehensive study of the report accomplished synthetic routes of pyrimidine analogs and their target-specific antiviral potential. The present review article covers literature from 2018 to 2022.

FDA approved five-membered ring fused pyrimidine-based derivatives and their biological properties

Pyrimidines-based drugs are one of the most important drugs for novel and recurring viruses, including the coronavirus. This chapter deals with 41 FDA-approved five-membered ring fused pyrimidine-based drugs, their synthetic strategies, and pharmacological activities. © 2023 Elsevier Ltd. All rights reserved.

Synthesis of new 3-acetyl-1,3,4-oxadiazolines combined with pyrimidines as antileishmanial and antiviral agents.

A new series of 3-acetyl-1,3,4-oxadiazoline hybrid molecules was designed and synthesized using a condensation between acyclonucleosides and substituted phenylhydrazone. All intermediates and final products were screened against Leishmania donovani, a Protozoan parasite and against three viruses SARS-CoV-2, HCMV and VZV. While no significant activity was observed against the viruses, the intermediate with 6-azatymine as thymine and 5-azathymine-3-acetyl-1,3,4-oxadiazoline hybrid exhibited a significant antileishmanial activity. The later compound was the most promising, exhibiting an IC50 value at 8.98 µM on L. donovani intramacrophage amastigotes and a moderate selectivity index value at 2.4.

Chapter 5 - FDA approved five-membered ring fused pyrimidine-based derivatives and their biological properties

Pyrimidines-based drugs are one of the most important drugs for novel and recurring viruses, including the coronavirus. This chapter deals with 41 FDA-approved five-membered ring fused pyrimidine-based drugs, their synthetic strategies, and pharmacological activities.

Inhibitors of Nucleotide Biosynthesis as Candidates for a Wide Spectrum of Antiviral Chemotherapy.

Emerging and re-emerging viruses have been a challenge in public health in recent decades. Host-targeted antivirals (HTA) directed at cellular molecules or pathways involved in virus multiplication represent an interesting strategy to combat viruses presently lacking effective chemotherapy. HTA could provide a wide range of agents with inhibitory activity against current and future viruses that share similar host requirements and reduce the possible selection of antiviral-resistant variants. Nucleotide metabolism is one of the more exploited host metabolic pathways as a potential antiviral target for several human viruses. This review focuses on the antiviral properties of the inhibitors of pyrimidine and purine nucleotide biosynthesis, with an emphasis on the rate-limiting enzymes dihydroorotate dehydrogenase (DHODH) and inosine monophosphate dehydrogenase (IMPDH) for which there are old and new drugs active against a broad spectrum of pathogenic viruses.

Antibacterial, antifungal and antiviral activities of pyrimido[4,5- d]pyrimidine derivatives through computational approaches

Pyrimido[4,5-d]pyrimidine conveys antimicrobial activity against various micro pathogens having functionalized properties. As a result, this study has designed to illustrate the antibacterial, antifungal, and antiviral properties of pyrimido[4,5-d]pyrimidine. First of all, these structures have been optimized from the characterization of synthesis for calculating chemical descriptors by DFT. Next, the auto docking and target docking against 12 proteins, such as Pseudomonas aeruginosa (2Y0H), Bacillus cereus (1AH7), Escherichia coli (6DR3), Shigella dysenteriae (3FHH) Salmonella typhi (3FHU), Aspergillus niger (1ACZ), Aspergillus flavus (1XY3), Rhizomucor miehei (4WTP), Candida auris (6U8J), three proteins of SARS-CoV-2 (7T9J, 7T9L, and 7TB4) were performed for the determination of binding sites and binding affinity. One FDA approved drug (Ampicillin) has docked against 12 proteins while the Bacillus cereus (Bacteria), Aspergillus flavus (Fungus), and SARS-CoV-2, 7T9L (Omicron) are obtained the best binding affinity after docking. The most common residues are the PHE-66, ARG-176 and VAL-124 for Bacillus cereus, Aspergillus flavus and SARS-CoV-2, Omicron (7T9L), respectively, as they blocked the active sites by the ligands as inhibitors. It is revealed that this study contained both auto docking and target docking whereas the binding affinity of auto docking is that the binding affinity for auto docking is higher than target docking. Finally, among the nine compounds, three compounds show outstanding results against bacteria, fungus and virus. At last, molecular dynamics were performed to check the stability and validation of the docked complex and quantum calculations obtained the molecular properties, as well as ADMET, pharmacokinetics, Lipinski Rule and QSAR data.

Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury.

Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion. We identified lead compound 9g that inhibits IL-6 secretion with IC50 of 3.72 µM without apparent cytotoxicity and with minimal suppression of macrophage phagocytosis in contrast to dexamethasone. In a mouse model of LPS-induced acute lung injury, 30 mg/kg i.p. 9g ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of 9g. Treatment with compound 9g prevented the migration of CD68+ macrophages and the incidence of hemorrhage. Hence, we have identified a promising pharmacological approach for the treatment of acute lung injury that may hold promise for the development of novel drugs against cytokine-mediated complications of bacterial and viral infections.

1,2,4-Triazolo[1,5-a]pyrimidines: Efficient one-step synthesis and functionalization as influenza polymerase PA-PB1 interaction disruptors.

In the search for new anti-influenza virus (IV) compounds, we have identified the 1,2,4-triazolo[1,5-a]pyrimidine (TZP) as a very suitable scaffold to obtain compounds able to disrupt IV RNA-dependent RNA polymerase (RdRP) PA-PB1 subunits heterodimerization. In this work, in order to acquire further SAR insights for this class of compounds and identify more potent derivatives, we designed and synthesized additional series of analogues to investigate the role of the substituents around the TZP core. To this aim, we developed four facile and efficient one-step procedures for the synthesis of 5-phenyl-, 6-phenyl- and 7-phenyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines, and 2-amino-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol. Two analogues having the ethyl carboxylate moiety at the C-2 position of the TZP were also prepared in good yields. Then, the scaffolds herein synthesized and two previous scaffolds were functionalized and evaluated for their anti-IAV activity, leading to the identification of compound 22 that showed both anti-PA-PB1 (IC50 = 19.5 µM) and anti-IAV activity (EC50 = 16 µM) at non-toxic concentrations, thus resulting among the most active TZP derivatives reported to date by us. A selection of the synthesized compounds, along with a set of in-house available analogues, was also tested against SARS-CoV-2. The most promising compound 49 from this series displayed an EC50 value of 34.47 µM, highlighting the potential of the TPZ scaffold in the search for anti-CoV agents.

An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts.

[Figure: see text].