Synthesis and anti-influenza activity of five member heterocycles containing compounds: a mini review

This survey covers the literature data published on the chemistry of synthesis of five membered heterocycles containing compounds that show anti-influenza activity. Furthermore, we made a brief review of the anti-influenza activity of these compounds. We believe that this review will be a useful resource for researchers working on developing of anti-influenza agents


Introduction
Influenza is a viral infection caused by various strains of the influenza virus, characterized by a highly contagious, acute respiratory syndrome.][3][4] Seasonal influenza is characterized by a sudden onset of fever, cough, headache, muscle and joint pain, severe malaise, sore throat, and a runny nose.Most people recover from fever and other symptoms within a week without requiring medical attention.But influenza can cause severe illness or death especially in people at high risk.Hospitalization and death occur mainly among high-risk groups such as children, elderly patients, patients with chronic respiratory diseases, and pregnant women.Worldwide, these epidemics are estimated to affect 5%-10% of the world's population every year, producing about 3 to 5 million cases of severe illness, and about 290 000 to 650 000 respiratory deaths. 5reventing both the disease and complications can be achieved by vaccination.If treatment with antivirals is administered without delay, the risk of severe complications can be reduced; however, many virus strains develop high resistance and current drugs lose efficacy, so recently, there has been great interest in developing new remedies for combating influenza. 5,6ive-membered heterocyclic compounds have shown a wide range of biological activities, 7 namely thiadiazoles, thiazoles, 1,3,4-oxadiazoles, triazoles, [8][9][10][11][12][13][14][15][16][17][18][19][20][21] in addition to the benzimidazole ring. 22They have been used as scaffolds for the synthesis of a wide range of agents with versatile activities including antibacterial, 23,24 antifungal, 25,26 analgesic, anti-inflammatory, 17 anticancer 27,28 and antihypertensive activity. 29][32][33][34][35][36] Many anti-influenza drugs contain five-membered heterocyclic rings in their structure (Figure 1).Nucleozin contains oxazole ring. 37A loading dose and short-term administration of oral ribavirin significantly improved symptoms and signs of influenza type A or B infection, 38 ribavirin contains triazole ring in its structure.Viramidine, the 3-carboxamidine derivative of ribavirin, is effective against a spectrum of influenza A and B and it also contains triazole moiety in its structure. 39Verdinexor, a triazole containing drug is a selective inhibitor of nuclear export, reduces influenza A virus replication in vitro and in vivo. 40Originally developed and commercialized as an antiprotozoal agent, Nitazoxanide was later identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. 41This review article describes the synthesis and pharmacological activity of new medications under study that contain five-membered heterocyclic rings and show potential benefits in the treatment of influenza.

Thiazoles
In 2020, Zhao et al. reported a series of novel thiazoles derived from an FDA-approved drug, nitazoxanide, (Scheme 1) with antiviral activity against influenza and a broad range of viruses.The preferred candidates compounds 1 and 2 showed significantly enhanced anti-influenza virus potentials, with 10-fold improvement compared to results with nitazoxanide, and were effective against a variety of influenza virus subtypes including oseltamivir-resistant strains.Notably, the combination using compounds 1, 2 and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effects against oseltamivir-resistant strains.Compound 1 was made by coupling of ethyl chloroformate and tizoxanide in N,N-dimethyl acetamide and CH3CN, while compound 2 was formed as coupling product of 1-butanesulfonyl chloride and tizoxanide in tetrahydrofuran as shown in Scheme 1. 42

Scheme 1
In 2019, Yarovaya et al. synthesized a series of novel camphecene analogues including the introduction of heterocyclic moieties in place of the terminal hydroxyl group of camphecene.All compounds were tested for cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells.Among the tested compounds, compounds 4, 5 demonstrated high antiviral activity, with compound 4 showing much less cytotoxicity than other synthesized compounds.Scheme 2 shows the synthesis of the target compounds, where camphecene was treated with phosphorous bromide (PBr3) in diethyl ether to produce the bromo intermediate 3 that was used directly in further reactions.Key compounds 4, 5 were prepared by nucleophilic substitution of secondary thiols with the bromo compound 3 in the presence of potassium carbonate and 1,8diazabicyclo[5,4,0]undec-7-ene (DBU) in acetonitrile as a solvent. 43

Scheme 2
Wang reported the synthesis of a series of novel 4,2-bisheterocycle tandem simplified derivatives of the cytotoxic heptapeptide compound Leucamide A, consisting of a methyloxazole and thiazole subunits.Many of these simplified compounds were found to effectively inhibit the human influenza A virus.Several analogues exhibited moderate biological activity and could serve as leads for further optimizations for antiviral research.Compounds A or B were treated with acyl chloride to afford the target compounds 6 and 7 as scheme 3 shows. 44heme 3 AUTHOR(S)

Oxadiazoles
Oxadiazole-linked heterocycles showed moderate to strong anti-influenza activity as follows.
Hala et al. in 2020 reported the synthesis of new oxadiazole derivatives for exploring their activity against avian influenza.The reaction of the acid hydrazide 9 with carbon disulfide in presence of potassium hydroxide in ethanol afforded the oxadiazole derivative 10 which showed moderate antiviral activity against avian influenza virus H5N1. 45

Scheme 5
We have reported a novel series of oxadiazole-based scaffolds that were evaluated in vitro against the highly pathogenic influenza H5N1.Four compounds 16b,c, 23b,e showed excellent anti-influenza activity with the oxadiazole derivative having p-tolyl at position 5 of the oxadiazole 16c being the most active showing 100% inhibition at 100 μg/μl with an IC50= 39 μg/μl.The oxadiazole derivatives 16a-c were synthesized through cyclization of the acid 14 to the final oxadiazole after heating with different acid hydrazides in phosphorus oxychloride as in scheme 6. 47 Scheme 7 shows the synthesis of the oxadiazoles 23a-f starting with the ester 17 that was produced by esterification of 4-chlorobenzoic acid, then reaction with hydrazine hydrate to furnish the acid hydrazide 18.The produced acid hydrazide was cyclized by refluxing with CS2/ KOH in ethanol to afford the 2-thiooxadiazole derivative 19 which underwent nitration using a mixture of concentrated HNO3 and concentrated H2SO4 furnishing the nitro compound 20 in good yield (68%).Alkylation of the produced nitro compound 20 with various alkyl halides in DMF and in presence of K2CO3 at room temperature produced compounds 21a-c.These compounds were further aminated using benzyl or phenethylamine to obtain compounds 23a-f.Scheme 6 Scheme 7 AUTHOR(S)

Scheme 8
It is well known that the development of entry inhibitors is a promising approach to the inhibition of the influenza virus.In 2019, Yangging et al. used oleanolic acid (OA) which was discovered as a mild influenza hemagglutinin (HA) inhibitor.Herein, as a further study, they reported the preparation of a series of OAsaccharide conjugates via the CuAAC reaction, and the anti-influenza activity of these compounds was evaluated in vitro.Among them, compound 30, an OA-glucose conjugate, showed a significantly increased anti-influenza activity with an IC50 of 5.47 µM, and no obvious cytotoxic effect on MDCK cells was observed at 100 mM.Hemagglutination inhibition assay and docking experiment indicated that compound 30 might interfere with influenza virus infection by acting on HA protein.Broad-spectrum anti-influenza experiments showed 30 to be robustly potent against five different strains, including influenza A and B viruses, with IC50 values at the low micromolar level.Overall, this finding further extends the utility of OA-saccharide conjugates in anti-influenza virus drug design. 49

Scheme 9
The influenza virus nucleoprotein (NP) is a perfect target for anti-influenza drug research Nucleozin and its related derivatives were found to act as NP inhibitors showing anti-influenza activity.Utilizing Nucleozin as a lead molecule, Huimin et al. in 2012 successfully designed and synthesized a series of 1H-1,2,3-triazole-4carboxamide derivatives as new anti-influenza A virus agents.The most potent compound 35 inhibited the replication of various H3N2 and H1N1 influenza A virus strains.Further computational studies and mechanism investigation approved that compound 35 can directly target nucleoprotein of influenza A virus to inhibit its nuclear accumulation.The synthetic pathway of compound 35 is illustrated in scheme 10. 50n our search for effective anti-influenza agents, we synthesized a series of triazole-linked heterocycles, the newly synthesized compounds were tested for their activity against the highly pathogenic avian influenza virus H5N1.The new compounds showed moderate to excellent antiviral activity.

Thiadiazoles
The thiadiazole derivatives synthesized by our group were tested for their activity against avian influenza and showed excellent activity. 47heme 13

Pyrazoles
While in the medicinal chemistry field, only limited reports have appeared involving the study of the antiinfluenza activity of the pyrazole-containing compounds.Shin et al. searched for novel anti-influenza inhibitors using a cell-based neutralization assay.After screening 20,800 randomly selected compounds, they found that BPR1P0034 (figure 2) has sub-micromolar antiviral activity.Lead optimization and a structure-activity analysis were used to improve potency.Time-of-addition assay was performed to target an event in the virus life cycle.BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and showed potent (sub-μM) antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agents. 51

Imidazoles
In 2015, Wang et al. designed and synthesized a series of new substituted phenyl-coupled heterocyclic ethyl amide derivatives as anti-influenza agents.The activities of these compounds were investigated and compared to those of the commercial antiviral drugs (Arbidol and Ribavirin) against influenza.Among these new compounds exhibiting moderate levels of antiviral activity against influenza A, compounds 52a-c are the most effective ones, and are as efficacious as the positive control Ribavirin and even much more effective than Ingavirin and Arbidol, indicating that they can be lead candidates for further exploration.These results are also consistent with the docking study results in terms of the design of compounds targeting influenza A via viral nucleoprotein.
The synthesis of the target compounds is shown in scheme 14.To the heterocyclic ethylamine hydrochloride, a solution of NaOH was added in ethanol and stirred at room temperature for 1 h.After filtration, the filtrate was evaporated to dryness and redissolved in THF.2-Chloro-4-nitrobenzoic acid and IBCF were stirred in an ice bath for 30 minutes and followed by the addition of the corresponding free amine in THF, and NMM was added, successively, stirred overnight to obtain the target compounds. 52Scheme 14

Tetrazoles
Hit compounds with anti-influenza virus activity were selected by in silico screening and tested to determine their anti-influenza virus activities via cell-based screening.Potent compounds with anti-influenza virus activities (MIC value <20μM) containing tetrazole moiety are shown in figure 3