Sulfonamides with Heterocyclic Periphery as Antiviral Agents

Sulfonamides are the basic motifs for a whole generation of drugs from a large group of antibiotics. Currently, research in the field of the new sulfonamide synthesis has received a “second wind”, due to the increase in the synthetic capabilities of organic chemistry and the study of their medical and biological properties of a wide spectrum of biological activity. New reagents and new reactions make it possible to significantly increase the number of compounds with a sulfonamide fragment in combination with other important pharmacophore groups, such as, for example, a wide class of N-containing heterocycles. The result of these synthetic possibilities is the extension of the activity spectrum—along with antibacterial activity, many of them exhibit other types of biological activity. Antiviral activity is also observed in a wide range of sulfonamide derivatives. This review provides examples of the synthesis of sulfonamide compounds with antiviral properties that can be used to develop drugs against coxsackievirus B, enteroviruses, encephalomyocarditis viruses, adenoviruses, human parainfluenza viruses, Ebola virus, Marburg virus, SARS-CoV-2, HIV and others. Since over the past three years, viral infections have become a special problem for public health throughout the world, the development of new broad-spectrum antiviral drugs is an extremely important task for synthetic organic and medicinal chemistry. Sulfonamides can be both sources of nitrogen for building a nitrogen-containing heterocyclic core and the side chain substituents of a biologically active substance. The formation of the sulfonamide group is often achieved by the reaction of the N-nucleophilic center in the substrate molecule with the corresponding sulfonylchloride. Another approach involves the use of sulfonamides as the reagents for building a nitrogen-containing framework.


Introduction
N-heterocycles and linear products synthesized from sulfonamides or containing a sulfonamide fragment in the side chain are important objects for studying biological activity. Traditionally, sulfonamides are primarily considered as antibacterial agents; however, among these substances one can find not only effective antibiotics [1,2], but also compounds with very different activities: oral hypoglycemic [3,4], antitumor [3,5], antiviral [6][7][8][9], antiepileptic [10], antihypertensive [11], antiprotozoal [12], antifungal [13], anticancer [14][15][16], anti-inflammatory [17], diuretic [18], butyrylcholinesterase inhibitors (anti-Alzheimer's disease activity) [19], MAO-B specific inhibitors (activity in the treatment of neurodegenerative disorders such as Parkinson's disease) [20], COX-2 inhibitors (therapy of inflammatory disease) [21], etc. Recent advances in the medicinal chemistry of sulfonamides showed the possibilities of new unique drug design. Sulfonamides are of particular importance in the synthesis of carbonic anhydrase inhibitors, which are used, for example, in combined chemotherapy for cancer [22]. Heterocyclic sulfonamides acts as hCA IV (as drug targets) inhibitors [23]. Pyrrolidine-containing sulfonamides (hCA IV inhibitors) are promising drugs for the treatment of glioma [23]. Sulfonamide hCA VII inhibitors are used in the complex therapy of HIV-infection. The N-acylsulfonamide form of of the prodrug Elsulfavirin selectively inhibits hCA VII to treat neurological complications of HIV infection [24]. Sulfonamide-containing 1,3-oxazoles and thiophenes show cytosolic CA I and CA II inhibition in the picomolar concentrations with extremely high selectivity [25]. Obtained compounds can currently be considered as the most potential basic structures of CA inhibitors for the synthesis of a wide range of drugs [25]. The authors of [26] obtained next-generation sulfonamide-containing carbonic anhydrase inhibitors that demonstrated high and selective inhibition effect of glaucoma-related hCA II, high hydrophilicity and the possibility of conjugation to sustained-release nanoparticles. Even at the initial stage of research, 5-(sulfamoyl)thien-2-yl 1,3-oxazoles (eye drops, 1% solution) showed an intraocular pressure reduction similar to the clinically used 2% solution of dorzolamide [26]. Sulfonamide derivatives often do not require complex functionalization of substituents [27], that greatly facilitates the synthesis of compounds used in the treatment of a wide range of diseases. It is widely known that nitrogen-containing heterocycles are the part of a large number of drugs of synthetic and natural origin [28,29]. Combining sulfonamide and N-heterocyclic pharmacophore groups in a molecule is one of the effective approaches to the synthesis of broad-spectrum drugs.

Antiviral Sulfonamide Derivatives
In their work, [30] presented the synthesis of chiral N-heterocycles based on arylsulfonamides. The reactions were diastereoselective and enantioselective. Compounds 3 and 6 were obtained by the classical method for sulfonamide chemistry, which consists in the treatment of amines (in this case, bicyclic amines 2 or 5) with available aryl-substituted sulfonyl chlorides (1 or 4). Substrates 2 and 5 were obtained by a stereoselective aza-Diels-Alder reaction (cyclopentadiene with in situ generated Shiff base reaction [30,31]). The most significant antiviral activity of compounds 3 and 6 was observed against EMCV with IC50 = 22.0 ± 2.6 µ M and IC50 = 18. The reactions were diastereoselective and enantioselective. Compounds 3 and 6 were obtained by the classical method for sulfonamide chemistry, which consists in the treatment of amines (in this case, bicyclic amines 2 or 5) with available aryl-substituted sulfonyl chlorides (1 or 4). Substrates 2 and 5 were obtained by a stereoselective aza-Diels-Alder reaction (cyclopentadiene with in situ generated Shiff base reaction [30,31]). The most significant antiviral activity of compounds 3 and 6 was observed against EMCV with IC 50 = 22.0 ± 2.6 µM and IC 50  Camphor derivatives containing heterocyclic fragments of the sulfonamide nitrogen atom were obtained in a similar way. The compounds exhibit antiviral activity against filoviruses (Ebola and Marburg viruses) [32] (Scheme 2): Scheme 2. The synthesis of N-heterocycle-containing (1S)-(+)-camphor-10-sulfonamide derivatives possessing an activity against filoviruses. Compound 8 was obtained by the reaction of camphor-substituted sulfonyl chlorides with the corresponding N-nucleophiles in the presence of Et3N in CH2Cl2. In the study of biological activity, sertraline was used as a reference drug, which has shown its efficacy in EBOV therapy. The resulting sulfonamide, 8, containing morpholine and triazole fragments, exhibited inhibitory activity against EBOV glycoproteins comparable to that of sertraline. Thus, as suggested by the authors of [17], the approach based on the synthesis of N-heterocyclic sulfonamides containing bicyclic terpenoid, camphor or borneol moieties is promising for the inhibitors research against dangerous viral infections [32]. Analysis of the inhibitory activity of 8 against glycoproteins showed that the minimum IC50 value was discovered for piperidine-substituted sulfonamides. This information is consistent with the results published earlier in [33], where a borneol derivative containing an ester group and a piperidine fragment was obtained and characterized. The results showed a good biological activity inhibiting MARV intrusion into the cell [33].
Morpholine-substituted sulfonamide 17 was synthesized, which exhibited biological activity against avian paramyxovirus (APMV-1) [34] (Scheme 3): Compound 8 was obtained by the reaction of camphor-substituted sulfonyl chlorides with the corresponding N-nucleophiles in the presence of Et 3 N in CH 2 Cl 2 . In the study of biological activity, sertraline was used as a reference drug, which has shown its efficacy in EBOV therapy. The resulting sulfonamide, 8, containing morpholine and triazole fragments, exhibited inhibitory activity against EBOV glycoproteins comparable to that of sertraline. Thus, as suggested by the authors of [17], the approach based on the synthesis of N-heterocyclic sulfonamides containing bicyclic terpenoid, camphor or borneol moieties is promising for the inhibitors research against dangerous viral infections [32]. Analysis of the inhibitory activity of 8 against glycoproteins showed that the minimum IC 50 value was discovered for piperidine-substituted sulfonamides. This information is consistent with the results published earlier in [33], where a borneol derivative containing an ester group and a piperidine fragment was obtained and characterized. The results showed a good biological activity inhibiting MARV intrusion into the cell [33].
Morpholine-substituted sulfonamide 17 was synthesized, which exhibited biological activity against avian paramyxovirus (APMV-1) [ Compound 8 was obtained by the reaction of camphor-substituted sulfonyl chlorides with the corresponding N-nucleophiles in the presence of Et3N in CH2Cl2. In the study of biological activity, sertraline was used as a reference drug, which has shown its efficacy in EBOV therapy. The resulting sulfonamide, 8, containing morpholine and triazole fragments, exhibited inhibitory activity against EBOV glycoproteins comparable to that of sertraline. Thus, as suggested by the authors of [17], the approach based on the synthesis of N-heterocyclic sulfonamides containing bicyclic terpenoid, camphor or borneol moieties is promising for the inhibitors research against dangerous viral infections [32]. Analysis of the inhibitory activity of 8 against glycoproteins showed that the minimum IC50 value was discovered for piperidine-substituted sulfonamides. This information is consistent with the results published earlier in [33], where a borneol derivative containing an ester group and a piperidine fragment was obtained and characterized. The results showed a good biological activity inhibiting MARV intrusion into the cell [33].
Morpholine-substituted sulfonamide 17 was synthesized, which exhibited biological activity against avian paramyxovirus (APMV-1) [34] (Scheme 3):  When tested, sulfonamide 17 was shown to exhibit three times higher antiviral activity against APMV-1 than ribavirin, a commonly available antiviral drug [34]. The multistep synthesis of compound 17 is shown in the Scheme 3. 3,3-Dimethylcyclohexanone 9 was chosen as the starting substrate for the synthesis of sulfonamide 17; its treatment with dimethyl carbonate in the presence of sodium hydride in THF gave carboxylate 10. Compound 10 was heterocyclized in the presence of S-methylisothiourea in water followed by treatment with KOH to form tetrahydroquinazoline-4 11 (these steps of the synthesis are described in [35,36]). The intermediate N-heterocycle 11 was further reacted with morpholine 12 on heating to 120 • C to give product 13 [37]. The synthesis of the target product 17 was completed by the substitution of the hydroxyl group for a chlorine atom in the presence of POCl 3 with the formation of product 14. Then the chlorine atom was substituted by piperazine to form compound 15 [38]. Compound 15 was further treated with sulfonylchloride 16 to give target product 17 [34].
Cyclic sulfonamide 22 (Scheme 4) described in [39] exhibits a specific type of biological activity against SARS-CoV-2. Compound 22 was a potential inhibitor of SARS-CoV-2, did not exhibit cytotoxicity, had an IC 50 = 0.8 µM and SI = 30.7. Heterocycle 22 showed good oral bioavailability (77%), metabolic stability and low binding to hERG. The study presented in [39] showed that heterocyclic sulfonamide 22 was a promising substance for the development of drugs-specifically, SARS-CoV-2 inhibitors [39]: When tested, sulfonamide 17 was shown to exhibit three times higher antiviral activity against APMV-1 than ribavirin, a commonly available antiviral drug [34]. The multistep synthesis of compound 17 is shown in the Scheme 3. 3,3-Dimethylcyclohexanone 9 was chosen as the starting substrate for the synthesis of sulfonamide 17; its treatment with dimethyl carbonate in the presence of sodium hydride in THF gave carboxylate 10. Compound 10 was heterocyclized in the presence of S-methylisothiourea in water followed by treatment with KOH to form tetrahydroquinazoline-4 11 (these steps of the synthesis are described in [35,36]). The intermediate N-heterocycle 11 was further reacted with morpholine 12 on heating to 120 °C to give product 13 [37]. The synthesis of the target product 17 was completed by the substitution of the hydroxyl group for a chlorine atom in the presence of POCl3 with the formation of product 14. Then the chlorine atom was substituted by piperazine to form compound 15 [38]. Compound 15 was further treated with sulfonylchloride 16 to give target product 17 [34].
Cyclic sulfonamide 22 (Scheme 4) described in [39] exhibits a specific type of biological activity against SARS-CoV-2. Compound 22 was a potential inhibitor of SARS-CoV-2, did not exhibit cytotoxicity, had an IC50 = 0.8 µ M and SI = 30.7. Heterocycle 22 showed good oral bioavailability (77%), metabolic stability and low binding to hERG. The study presented in [39] showed that heterocyclic sulfonamide 22 was a promising substance for the development of drugs-specifically, SARS-CoV-2 inhibitors [39]: Sulfonyl chloride 18 was selected as the starting substrate for the product 22 synthesis. Compound 18 was added to aqueous ammonia and refluxed for 1 h to form sulfonamide 19. The methyl group in 19 was oxidized with KMnO4 in a basic medium to form compound 20, which was dehydrated to saccharin 21 under the action of sulfuric acid. Next, compound 21 was heterocyclized and functionalized in a three-step sequence to form product 22, as shown in Scheme 4 [39].
Hydantoin derivatives are important biologically active substances, many of which are well studied and have been used for several decades to obtain drugs [40,41]. Hydantoins are often considered as N-heterocycles containing an α-amino acid fragment and urea, which causes the presence of various types of biological activity, that can be easily changed by varying substituents [42,43]. Hydantoin-substituted sulfonamides showed antiviral activity [44,45]  Sulfonyl chloride 18 was selected as the starting substrate for the product 22 synthesis. Compound 18 was added to aqueous ammonia and refluxed for 1 h to form sulfonamide 19. The methyl group in 19 was oxidized with KMnO 4 in a basic medium to form compound 20, which was dehydrated to saccharin 21 under the action of sulfuric acid. Next, compound 21 was heterocyclized and functionalized in a three-step sequence to form product 22, as shown in Scheme 4 [39].
Hydantoin derivatives are important biologically active substances, many of which are well studied and have been used for several decades to obtain drugs [40,41]. Hydantoins are often considered as N-heterocycles containing an α-amino acid fragment and urea, which causes the presence of various types of biological activity, that can be easily changed by varying substituents [42,43]. Hydantoin-substituted sulfonamides showed antiviral activity [44,45]  Purine derivatives are rightly considered to be special structures for the study of properties in the field of medical and synthetic organic chemistry due to the wide presence of such fragments in natural compounds. Purines and fused purines are going to get a lot of attention for many years due to their interesting pharmacological properties in antiviral [46][47][48][49][50][51] and antimicrobial [52] drugs. By a simple reaction of 6-chloro-4,5-dihydro-7H-pu- strain AD169. The EC 50 value of the sulfonamide 28 was comparable to the EC 50 of the reference drugs (ganciclovir and cidofovir) [44,45].
Purine derivatives are rightly considered to be special structures for the study of properties in the field of medical and synthetic organic chemistry due to the wide presence of such fragments in natural compounds. Purines and fused purines are going to get a lot of attention for many years due to their interesting pharmacological properties in antiviral [46][47][48][49][50][51] and antimicrobial [52] drugs. By a simple reaction of 6-chloro-4,5-dihydro-7H-purine 29 with sulfamide derivative 30, a new compound 31 exhibiting biological activity was obtained. Such compounds are very promising for treating various viral infections [46] (Scheme 6): Scheme 5. The synthesis of antiviral sulfamides with a hydantoin fragment.
Product 28 was synthesized in two successive steps. At the first step, the amino group of polyfunctional amine 24 was attached to isocyanate 23. Intermediate adduct 25 underwent heterocyclization to compound 26 due to the presence of a CN-group in the structure. Then, intermediate 26 was recyclized to the target intermediate 27. Sulfonic chloride 27 was further treated with an excess of aliphatic primary or secondary amines to form Nheterocyclic sulfonamide 28. Compound 28 was effective against cytomegalovirus strain AD169. The EC50 value of the sulfonamide 28 was comparable to the EC50 of the reference drugs (ganciclovir and cidofovir) [44,45].
Purine derivatives are rightly considered to be special structures for the study of properties in the field of medical and synthetic organic chemistry due to the wide presence of such fragments in natural compounds. Purines and fused purines are going to get a lot of attention for many years due to their interesting pharmacological properties in antiviral [46][47][48][49][50][51] and antimicrobial [52] drugs. By a simple reaction of 6-chloro-4,5-dihydro-7H-purine 29 with sulfamide derivative 30, a new compound 31 exhibiting biological activity was obtained. Such compounds are very promising for treating various viral infections [46] (Scheme 6): The yields of compounds were about 80%. Pyrrole rings are part of porphyrins, hemoglobins and cytochromes. Compounds containing pyrrole and sulfonamide fragments could potentially exhibit various types of biological activity. As part of the study of methods for the synthesis of antiviral drugs based on sulfonamides, it is worth noting the unique reaction presented in Scheme 7. This reaction is a simple and effective method for obtaining substituted pyrrole 34 from primary sulfonamide 33 [53]: The yields of compounds were about 80%. Pyrrole rings are part of porphyrins, hemoglobins and cytochromes. Compounds containing pyrrole and sulfonamide fragments could potentially exhibit various types of biological activity. As part of the study of methods for the synthesis of antiviral drugs based on sulfonamides, it is worth noting the unique reaction presented in Scheme 7. This reaction is a simple and effective method for obtaining substituted pyrrole 34 from primary sulfonamide 33 [53]: The yields of the compounds were quantitative. The availability and low cost of the process is important for medicinal chemistry and the synthesis of biologically active nitrogen-containing heterocycles, given the presence of pharmacophore sulfonamide groups in the products. The reaction is applicable to a wide range of substrates, including arylsulfonamides, alkylsulfonamides 33 and various drug molecules containing sulfonamides. The formation of sulfonylpyrrole 34 proceeded via the reaction of sulfonamide and 2,5-dimethoxytetrahydrofuran (diMeOTHF) 32 in the presence of a catalytic amount of p-TsOH (similar to the reaction of sulfonylpyridinium salts [54]). The reaction was also carried out with microwave activation without solvent and additives at 150 °С [53]. The method may be of interest for the synthesis of antiviral drugs, since antiviral biological activity is known for sulfonamide-containing pyrroles [55].
The synthesis of small-molecule mimics involved in the interaction of the broadly neutralizing antibody 447-52D with the gp120 V3 loop was developed [56] (Scheme 8). The resulting 1,3,5-triazine framework 39 showed very good antiviral activity. The molecules have an IC50 below 5.0 μM. The study was revealed a promising molecular structure that can be further studied to produce powerful HIV-1 inhibitors aimed at virus entry.
In the work [56] was presented the synthesis of 1,3,5-triazine-substituted sulfonamide 39. The compound 39 showed good antiviral activity and had an IC50 below 5.0 μM. Product 39 was the basic molecular structure that can be used to synthesize inhibitors of HIV-1 virus entry into the cell (Scheme 8): Scheme 7. Preparation of substituted pyrroles from primary sulfonamides.
The yields of the compounds were quantitative. The availability and low cost of the process is important for medicinal chemistry and the synthesis of biologically active nitrogen-containing heterocycles, given the presence of pharmacophore sulfonamide groups in the products. The reaction is applicable to a wide range of substrates, including arylsulfonamides, alkylsulfonamides 33 and various drug molecules containing sulfonamides. The formation of sulfonylpyrrole 34 proceeded via the reaction of sulfonamide and 2,5-dimethoxytetrahydrofuran (diMeOTHF) 32 in the presence of a catalytic amount of p-TsOH (similar to the reaction of sulfonylpyridinium salts [54]). The reaction was also carried out with microwave activation without solvent and additives at 150 • C [53]. The method may be of interest for the synthesis of antiviral drugs, since antiviral biological activity is known for sulfonamide-containing pyrroles [55].
The synthesis of small-molecule mimics involved in the interaction of the broadly neutralizing antibody 447-52D with the gp120 V3 loop was developed [56] (Scheme 8). The resulting 1,3,5-triazine framework 39 showed very good antiviral activity. The molecules have an IC 50 below 5.0 µM. The study was revealed a promising molecular structure that can be further studied to produce powerful HIV-1 inhibitors aimed at virus entry.
neutralizing antibody 447-52D with the gp120 V3 loop was developed [56] (Scheme 8). The resulting 1,3,5-triazine framework 39 showed very good antiviral activity. The molecules have an IC50 below 5.0 μM. The study was revealed a promising molecular structure that can be further studied to produce powerful HIV-1 inhibitors aimed at virus entry.
In the work [56] was presented the synthesis of 1,3,5-triazine-substituted sulfonamide 39. The compound 39 showed good antiviral activity and had an IC50 below 5.0 μM. Product 39 was the basic molecular structure that can be used to synthesize inhibitors of HIV-1 virus entry into the cell (Scheme 8): Scheme 8. Preparation of tri-substituted antiviral s-triazine.
The synthesis of compound 39 was carried out by successive treatment of cyanuric chloride 35 with sulfanilamide and the corresponding amines under alkaline conditions with cooling to 0-4 °C or at room temperature in acetone or dioxane. The reaction proceeded by the mechanism of nucleophilic substitution. The product was isolated with a good yield [56]. In the work [56] was presented the synthesis of 1,3,5-triazine-substituted sulfonamide 39. The compound 39 showed good antiviral activity and had an IC 50 below 5.0 µM. Product 39 was the basic molecular structure that can be used to synthesize inhibitors of HIV-1 virus entry into the cell (Scheme 8): The synthesis of compound 39 was carried out by successive treatment of cyanuric chloride 35 with sulfanilamide and the corresponding amines under alkaline conditions with cooling to 0-4 • C or at room temperature in acetone or dioxane. The reaction proceeded by the mechanism of nucleophilic substitution. The product was isolated with a good yield [56].
Thiosemicarbazones are widely used substrates in the synthesis of substituted N-heterocycles and antiviral compounds with a wide spectrum of antiviral activity against a number of DNA and RNA viruses. Derivatives of thiosemicarbazones are known to exhibit inhibitors of RNA replication of hepatitis C virus and HIV-1 [59][60][61]. There were known sulfonamide derivatives of thiosemicarbazone 47 with antiviral properties, which had fewer side effects, rapid clearance rate or less incidence of relapse [62] (Scheme 10): The pyrimidine compound represented the best candidate to develop broad-spectrum antiflavivirus agents after a focused optimization to further increase its potency and ADME properties [57].
Thiosemicarbazones are widely used substrates in the synthesis of substituted N-heterocycles and antiviral compounds with a wide spectrum of antiviral activity against a number of DNA and RNA viruses. Derivatives of thiosemicarbazones are known to exhibit inhibitors of RNA replication of hepatitis C virus and HIV-1 [59][60][61]. There were known sulfonamide derivatives of thiosemicarbazone 47 with antiviral properties, which had fewer side effects, rapid clearance rate or less incidence of relapse [62] (Scheme 10): Molecules 2023, 28, 51

of 15
The pyrimidine compound represented the best candidate to develop broad-spectrum antiflavivirus agents after a focused optimization to further increase its potency and ADME properties [57].
Thiosemicarbazones are widely used substrates in the synthesis of substituted N-heterocycles and antiviral compounds with a wide spectrum of antiviral activity against a number of DNA and RNA viruses. Derivatives of thiosemicarbazones are known to exhibit inhibitors of RNA replication of hepatitis C virus and HIV-1 [59][60][61]. There were known sulfonamide derivatives of thiosemicarbazone 47 with antiviral properties, which had fewer side effects, rapid clearance rate or less incidence of relapse [62] (Scheme 10): Scheme 10. Preparation of 5-(arylazo) salicylaldehyde-thiosemicarbazone antiviral derivatives.
The expected anti-BVDV (bovine viral diarrhea virus) property of the synthesized derivatives was tested. The results indicated that the presence of sulphonamido-at arylazo and ethyl-, phenyl-at N-(4)-thiosemicarbazone moieties exhibited a potent anti-BVDV activity [62].
In the treatment of severe infections such as HIV-1, combined antiretroviral therapy, including non-nucleoside reverse transcriptase inhibitors is used. This approach has shown to be effective in suppressing viral replication. There are sulfonamide-containing N-heterocycles, which have shown their effectiveness in antiretroviral therapy. The expected anti-BVDV (bovine viral diarrhea virus) property of the synthesized derivatives was tested. The results indicated that the presence of sulphonamido-at arylazo and ethyl-, phenyl-at N-(4)-thiosemicarbazone moieties exhibited a potent anti-BVDV activity [62].
In the treatment of severe infections such as HIV-1, combined antiretroviral therapy, including non-nucleoside reverse transcriptase inhibitors is used. This approach has shown to be effective in suppressing viral replication. There are sulfonamide-containing N-heterocycles, which have shown their effectiveness in antiretroviral therapy. Compound 55 exhibited HIV-1 inhibitory activity in some cases with greater efficiency than the reference drugs (nevirapine and efavirenz) [63]. The multistage synthesis of product 55 started with the reaction of 2-nitroaniline 48 with 3,5-dimethylbenzenesulfonyl chloride 49 in DMF and in the presence of sodium hydride as a catalyst. In the resulting product 50, the nitro group was further reduced to form the corresponding N-(2aminophenyl)-3,5-dimethylbenzenesulfonamide 51 according to the classical method in the presence of zinc and hydrochloric acid in ethanol. In the next step, compound 51 was heterocyclized in the presence of 1,1-thiocarbonyldiimidazole 52 to give 1-(3,5-dimethylphenylsulfonyl)-1,3-dihydro-2H-benzimidazole-2-thione 53. At the last stage, the intermediate heterocycle 53 was dissolved in DMF and treated with N-phenylacetamide 54 in the presence of K2CO3 to give benzimidazole 55. The last reaction was carried out at room temperature overnight [63].
In the work [64] was presented a simple methodology for the synthesis of quinolinesubstituted sulfonamide 60. The resulting compound 60 was tested against four viruses that infect poultry. Analysis of antiviral activity and IC50 values showed that sulfonamide 60 is active against Newcastle disease virus (NDV), infectious bursal disease virus (IBDV), avian influenza virus subtype H9N2 (AIV) and infectious bronchitis virus (IBV) (Scheme 12): Scheme 11. The synthesis new non-nucleoside reverse transcriptase inhibitors active against. wildtype and mutant HIV-1 strains.
Compound 55 exhibited HIV-1 inhibitory activity in some cases with greater efficiency than the reference drugs (nevirapine and efavirenz) [63]. The multistage synthesis of product 55 started with the reaction of 2-nitroaniline 48 with 3,5-dimethylbenzenesulfonyl chloride 49 in DMF and in the presence of sodium hydride as a catalyst. In the resulting product 50, the nitro group was further reduced to form the corresponding N-(2-aminophenyl)-3,5-dimethylbenzenesulfonamide 51 according to the classical method in the presence of zinc and hydrochloric acid in ethanol. In the next step, compound 51 was heterocyclized in the presence of 1,1-thiocarbonyldiimidazole 52 to give 1-(3,5-dimethylphenylsulfonyl)-1,3-dihydro-2H-benzimidazole-2-thione 53. At the last stage, the intermediate heterocycle 53 was dissolved in DMF and treated with N-phenylacetamide 54 in the presence of K 2 CO 3 to give benzimidazole 55. The last reaction was carried out at room temperature overnight [63].
In the work [64] was presented a simple methodology for the synthesis of quinolinesubstituted sulfonamide 60. The resulting compound 60 was tested against four viruses that infect poultry. Analysis of antiviral activity and IC 50 values showed that sulfonamide 60 is The first step in the synthesis of sulfonamide 60 was the Knoevenagel condensation of barbituric acid and aldehyde 57, which proceeded with the formation of 5-(3-nitrobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione 58. Compound 58 underwent further heterocyclization with various sulfonamides 59 to form quinoline-substituted sulfonamide 60. The sulfanonamide derivative 60 showed high activity against influenza viruses H9N2, NDV and IBDV. The thiazole derivative 60 was active against NDV and IBDV strains. The lowest IC50 (0.001 mg) was obtained in a study of biological activity against the H9N2 virus. The oxazole derivative 60 was active against all viruses except H9N2; the lowest IC50 value (0.01 mg) was shown for IBV. Guanidine-substituted sulfonamide 60 demonstrated the highest antiviral activity comparable to that of amantadine [64,65].
Calixarenes are cyclic oligomers synthesized from phenol and formaldehyde [66], that have been proposed as potential drug candidates [67,68]. Sulfanilamide derivatives bounded to the calix [4]arene 61 scaffold also showed potential antiviral activity [69]. It was reported that the introduction of the azo-group has improved more than 60% of the antibacterial activities of certain molecules [70]. At the moment, theoretical studies of biological activity have shown a high potential of as neuraminidase receptor inhibitors. The presence of an aza-group in the compound 62 suggested the possibility of synthesis of a number of nitrogen-containing heterocycles exhibiting antiviral activity [69]. The first step in the synthesis of sulfonamide 60 was the Knoevenagel condensation of barbituric acid and aldehyde 57, which proceeded with the formation of 5-(3nitrobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione 58. Compound 58 underwent further heterocyclization with various sulfonamides 59 to form quinoline-substituted sulfonamide 60. The sulfanonamide derivative 60 showed high activity against influenza viruses H9N2, NDV and IBDV. The thiazole derivative 60 was active against NDV and IBDV strains. The lowest IC 50 (0.001 mg) was obtained in a study of biological activity against the H9N2 virus. The oxazole derivative 60 was active against all viruses except H9N2; the lowest IC 50 value (0.01 mg) was shown for IBV. Guanidine-substituted sulfonamide 60 demonstrated the highest antiviral activity comparable to that of amantadine [64,65].
Calixarenes are cyclic oligomers synthesized from phenol and formaldehyde [66], that have been proposed as potential drug candidates [67,68]. Sulfanilamide derivatives bounded to the calix [4]arene 61 scaffold also showed potential antiviral activity [69]. It was reported that the introduction of the azo-group has improved more than 60% of the antibacterial activities of certain molecules [70]. At the moment, theoretical studies of biological activity have shown a high potential of as neuraminidase receptor inhibitors. The presence of an aza-group in the compound 62 suggested the possibility of synthesis of a number of nitrogen-containing heterocycles exhibiting antiviral activity [69]. The first step in the synthesis of sulfonamide 60 was the Knoevenagel condensation of barbituric acid and aldehyde 57, which proceeded with the formation of 5-(3-nitrobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione 58. Compound 58 underwent further heterocyclization with various sulfonamides 59 to form quinoline-substituted sulfonamide 60. The sulfanonamide derivative 60 showed high activity against influenza viruses H9N2, NDV and IBDV. The thiazole derivative 60 was active against NDV and IBDV strains. The lowest IC50 (0.001 mg) was obtained in a study of biological activity against the H9N2 virus. The oxazole derivative 60 was active against all viruses except H9N2; the lowest IC50 value (0.01 mg) was shown for IBV. Guanidine-substituted sulfonamide 60 demonstrated the highest antiviral activity comparable to that of amantadine [64,65].
Calixarenes are cyclic oligomers synthesized from phenol and formaldehyde [66], that have been proposed as potential drug candidates [67,68]. Sulfanilamide derivatives bounded to the calix [4]arene 61 scaffold also showed potential antiviral activity [69]. It was reported that the introduction of the azo-group has improved more than 60% of the antibacterial activities of certain molecules [70]. At the moment, theoretical studies of biological activity have shown a high potential of as neuraminidase receptor inhibitors. The presence of an aza-group in the compound 62 suggested the possibility of synthesis of a number of nitrogen-containing heterocycles exhibiting antiviral activity [69].    HAdV7)). For most of these viruses no specific drugs were found. Known drugs were used only to treat the symptoms of the disease (an exception is acyclovir) [72][73][74]. The compounds showed an impressive antiviral effect against three of the studied viruses (HSV-1, CBV4 and HAV) [71].
A new class of functionalized benzothiazole 71 bearing N-sulfonamide 2-pyridone derivatives was synthesized and its antiviral potency was exhibited [75]: Arylsulfonohydrazide 68 was used as the starting compound for the synthesis of N-arylsulfonylpyridone 71, that includes a benzothiazole fragment. The reaction of benzothiazole acetate 66 with hydrazine hydrate at room temperature gave acetohydrazide 67.  HAdV7)). For most of these viruses no specific drugs were found. Known drugs were used only to treat the symptoms of the disease (an exception is acyclovir) [72][73][74]. The compounds showed an impressive antiviral effect against three of the studied viruses (HSV-1, CBV4 and HAV) [71].
A new class of functionalized benzothiazole 71 bearing N-sulfonamide 2-pyridone derivatives was synthesized and its antiviral potency was exhibited [75]: Arylsulfonohydrazide 68 was used as the starting compound for the synthesis of Narylsulfonylpyridone 71, that includes a benzothiazole fragment. The reaction of benzothiazole acetate 66 with hydrazine hydrate at room temperature gave acetohydrazide 67. Antiviral activity against HSV-1, CBV4, HAV HM 175, HCVcc genotype 4 and HAdV7 viruses was studied for compound 76 [76]. In the case of HSV-1, the compound was found to exhibit excellent viral load reduction in the range of 70-90% with good IC50, CC50 and SI values compared to acyclovir. In the case of CBV4, a reduction in viral activity of more than 50% was shown. Compound 76 also had inhibitory activity against the Hsp90α protein with an IC50 in the range of 4.8-10.4 µ g/mL [76].
Derivatives of 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)benzene-1-sulfonamide 80 were synthesized, which exhibit inhibitory activity against the Dengue virus. Сompound  Antiviral activity against HSV-1, CBV4, HAV HM 175, HCVcc genotype 4 and HAdV7 viruses was studied for compound 76 [76]. In the case of HSV-1, the compound was found to exhibit excellent viral load reduction in the range of 70-90% with good IC 50 , CC 50 and SI values compared to acyclovir. In the case of CBV4, a reduction in viral activity of more than 50% was shown. Compound 76 also had inhibitory activity against the Hsp90α protein with an IC 50 in the range of 4.8-10.4 µg/mL [76].
Derivatives of 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)benzene-1-sulfonamide 80 were synthesized, which exhibit inhibitory activity against the Dengue virus. Compound 80 inhibited the NS2B-NS3 protease, which acts as a target for the development of anti-DENV2 agents. The resulting sulfonamide 80 showed IC 50 values for DENV2 protease inhibition of 48.2 and 121.9 µM, respectively [77]. Compound 80 was obtained as shown in Scheme 17: Scheme 16. The synthesis of sulfonamide-containing antiviral 2-pyrimidylbenzothiazoles. Pyrimidine 76 was synthesized by the reaction of N-arylsulfonylguanidine 75 with benzothiazole derivative 74 in the presence of alkali in dioxane in the absence of air. Intermediate alkene 74 was formed by the Michael reaction of nitrile 72 and aldehyde 73. Antiviral activity against HSV-1, CBV4, HAV HM 175, HCVcc genotype 4 and HAdV7 viruses was studied for compound 76 [76]. In the case of HSV-1, the compound was found to exhibit excellent viral load reduction in the range of 70-90% with good IC50, CC50 and SI values compared to acyclovir. In the case of CBV4, a reduction in viral activity of more than 50% was shown. Compound 76 also had inhibitory activity against the Hsp90α protein with an IC50 in the range of 4.8-10.4 µ g/mL [76].

Conclusions
Viral infections have attracted the close attention of the entire scientific community in every corner of the planet. The COVID-19 epidemic has confirmed the danger of drugresistant strains and made the task of developing new antiviral drugs more urgent than ever. The presented short review showed the main methodologies for the synthesis of antiviral derivatives of sulfonamides, which were obtained on the basis of N-containing heterocyclic structures. There is no doubt about the effect of the sulfonamide fragment on the antiviral properties of the obtained compounds. Moreover, sulfonamides can be both sources of nitrogen for building a nitrogen-containing heterocyclic core and the side chain substituents of a biologically active substance. The formation of the sulfonamide group is often achieved by the reaction of the N-nucleophilic center in the substrate molecule with the corresponding sulfonylchloride. This review provides examples of the synthesis of sulfonamide compounds with antiviral properties that can be used to develop drugs against EMCV, AdV5, HPIV, EBOV, MARV, APMV, SARS-CoV-2, HIV, DENV, ZIKV, BVDV, NDV, IBDV, H9N2, AIV, IBV, HSV, CBV, HAV, VYG, HCVcc and HAdV.  The phthalimide motif in compound 81 was hydrolyzed to form intermediate 82. Ester 82 was also hydrolyzed with refluxing in the presence NaOH to form compound 83 (yield 82%) [79].

Conclusions
Viral infections have attracted the close attention of the entire scientific community in every corner of the planet. The COVID-19 epidemic has confirmed the danger of drugresistant strains and made the task of developing new antiviral drugs more urgent than ever. The presented short review showed the main methodologies for the synthesis of antiviral derivatives of sulfonamides, which were obtained on the basis of N-containing heterocyclic structures. There is no doubt about the effect of the sulfonamide fragment on the antiviral properties of the obtained compounds. Moreover, sulfonamides can be both sources of nitrogen for building a nitrogen-containing heterocyclic core and the side chain substituents of a biologically active substance. The formation of the sulfonamide group is often achieved by the reaction of the N-nucleophilic center in the substrate molecule with the corresponding sulfonylchloride. This review provides examples of the synthesis of sulfonamide compounds with antiviral properties that can be used to develop drugs against EMCV, AdV5, HPIV, EBOV, MARV, APMV, SARS-CoV-2, HIV, DENV, ZIKV, BVDV, NDV, IBDV, H9N2, AIV, IBV, HSV, CBV, HAV, VYG, HCVcc and HAdV.
Funding: This work was supported by the Russian Science Foundation (project 22-13-00036).