Thiopyrano[2,3-d]Thiazoles as New Efficient Scaffolds in Medicinal Chemistry

This review presents the up to date development of fused thiopyranothiazoles that comprise one of the thiazolidine derivatives classes. Thiazolidine and thiazolidinone-related compounds belong to the widely studied heterocycles from a medicinal chemistry perspective. From the chemical point of view, they are perfect heterodienes to undergo hetero-Diels–Alder reaction with a variety of dienophiles, yielding regio- and diastereoselectively thiopyranothiazole scaffolds. The annealing of thiazole and thiopyran cycles in condensed heterosystem is a precondition for the “centers conservative” creation of the ligand-target binding complex and can promote a potential selectivity to biotargets. The review covers possible therapeutic applications of thiopyrano[2,3-d]thiazoles, such as anti-inflammatory, antibacterial, anticancer as well as aniparasitic activities. Thus, thiopyrano[2,3-d]thiazoles may be used as powerful tools in the development of biologically active agents and drug-like molecules.


Hetero-Diels-Alder Reaction as a Key Approach for the Synthesis of Thiopyrano[2,3-d]Thiazole Derivatives
The most effective approach to thiopyrano [2,3-d]thiazole system design is the use of the hetero-Diels-Alder reaction. Mentioned approach has been described for the first time by I.D. Komaritsa [18], N.A. Kassab et al. [19,20] who had successfully used 5-arylidene-4-thioxo-2-thiazolidinones (5arylideneisorhodanines) and 5-arylidene-2,4-thiazolidinedithiones (5-arylidenethiorhodanines) as heterodienes. Mentioned reagents contain in their structure α,β-unsaturated thiocarbonyl fragment similar to the 1-thio-1,3-butadiene which leads to their high reactivity in the [4+2]-сycloaddition reactions ( Figure 2). According to the molecular orbital theory, Diels-Alder reaction is based on the overlay of the diene's "HOMO" and dienophile's "LUMO". The important condition for this reaction is the presence of strong dienophile with electron acceptor properties to decrease energy difference between diene's "HOMO" and "LUMO" or "HOMO" of the dienophile. For these reasons reactions are highly regioselective and form products according to the molecular orbital theory.

Hetero-Diels-Alder Reaction as a Key Approach for the Synthesis of Thiopyrano[2,3-d]Thiazole Derivatives
The most effective approach to thiopyrano [2,3-d]thiazole system design is the use of the hetero-Diels-Alder reaction. Mentioned approach has been described for the first time by I.D. Komaritsa [18], N.A. Kassab et al. [19,20] who had successfully used 5-arylidene-4-thioxo-2-thiazolidinones (5-arylideneisorhodanines) and 5-arylidene-2,4-thiazolidinedithiones (5-arylidenethiorhodanines) as heterodienes. Mentioned reagents contain in their structure α,β-unsaturated thiocarbonyl fragment similar to the 1-thio-1,3-butadiene which leads to their high reactivity in the [4+2]-cycloaddition reactions ( Figure 2). According to the molecular orbital theory, Diels-Alder reaction is based on the overlay of the diene's "HOMO" and dienophile's "LUMO". The important condition for this reaction is the presence of strong dienophile with electron acceptor properties to decrease energy difference between diene's "HOMO" and "LUMO" or "HOMO" of the dienophile. For these reasons reactions are highly regioselective and form products according to the molecular orbital theory.
Sci. Pharm. 2018, 86, x 2 of 24 mentioned Michael acceptors properties ( Figure 1) [15][16][17]. The combination of thiazole and thiopyran cycles in condensed heterosystem is a precondition for the creation of "centers conservative" of the ligand-target binding complex and promotes potential selectivity to biotargets. Considering the mentioned arguments, the directed search for new chemotherapeutic agents among thiopyrano [2,3-d]thiazole derivatives is a justified and promising direction in modern medicinal chemistry. In this review, we tried to systematize the data on chemistry and pharmacology of thiopyrano [2,3-d]thiazoles from the perspective of medicinal and pharmaceutical chemistry.

Hetero-Diels-Alder Reaction as a Key Approach for the Synthesis of Thiopyrano[2,3-d]Thiazole Derivatives
The most effective approach to thiopyrano [2,3-d]thiazole system design is the use of the hetero-Diels-Alder reaction. Mentioned approach has been described for the first time by I.D. Komaritsa [18], N.A. Kassab et al. [19,20] who had successfully used 5-arylidene-4-thioxo-2-thiazolidinones (5arylideneisorhodanines) and 5-arylidene-2,4-thiazolidinedithiones (5-arylidenethiorhodanines) as heterodienes. Mentioned reagents contain in their structure α,β-unsaturated thiocarbonyl fragment similar to the 1-thio-1,3-butadiene which leads to their high reactivity in the [4+2]-сycloaddition reactions ( Figure 2). According to the molecular orbital theory, Diels-Alder reaction is based on the overlay of the diene's "HOMO" and dienophile's "LUMO". The important condition for this reaction is the presence of strong dienophile with electron acceptor properties to decrease energy difference between diene's "HOMO" and "LUMO" or "HOMO" of the dienophile. For these reasons reactions are highly regioselective and form products according to the molecular orbital theory.
The reaction of 5-arylideneisorhodanines with 2(5H)furanone yields mixtures of endo/exo adducts 16,17. (Scheme 5). Considering moderate diastereoselectivity of the process, the reaction can occur through endo or exo transition states resulting in different positions of the protons at C-8 of core heterocycle. Thus, the endo transition state leads to anti configuration, while the exo geometry results in syn configuration of the H-8 respectively. Endo and exo adducts can be separated by column chromatography [32]. Currently, the list of dienophiles for the synthesis of thiopyrano [2,3-d]thiazole derivatives has significantly expanded. Thus, the use of cynnamic acids [26] and their amides [27], aroylacrylic [28] and arylidene pyruvic [29] acids as well as dimethyl acetylenedicarboxylate [30], propiolic acid and its ethyl ester [26], acroleine [31], 2-norbornene [15] and 5-norbornene-2,3-dicarboxylic acid imides [16] as dienophiles allowed to obtain new thiopyrano[2,3-d]thiazoles 8-15 as promising biologically active compounds based on the "thiazolidinone" matrix (Scheme 4). It should be noted that the presence of chiral centers in the structure of thiopyrano [2,3-d]thiazole cycle causes certain features of stereochemistry in the hetero-Diels-Alder reaction. The given issue became the subject of an intense study considering the current trends in organic and medicinal chemistry. It was found that the above-mentioned [4+2]-cycloadditions are regio-and diastereoselective.

The Michael Reaction and Related Processes in the Synthesis of Thiopyrano[2,3-d]Thiazoles
The Michael reaction is one more effective approach to the synthesis of thiopyrano[2,3d]thiazoles (Scheme 15). Thus, the interaction of arylmethylene malononitrile and 3-substituted isorhodanines in the medium of absolute ethanol at the presence of triethylamine gave 5-amino-2oxo-7-phenyl-3,5,6,7-tetrahydro-2Н-thiopyrano[2,3-d]thiazole-6-carbonitriles 53 [42]. When studying the peculiarities of Michael addition of bicyclic 5-arylideneiso(thio)rhodanines 56 with malonodinitrile bis-thiopyrano[2,3-d]thiazole derivative 58 was obtained, which early was synthesized in the reaction of 1,4-bis-(2,2′-dicyanovinyl)-benzene 57 with two equivalents of isorhodanine. In the second case, formation of the derivative 58 occured as two-stage process When studying the peculiarities of Michael addition of bicyclic 5-arylideneiso(thio)rhodanines 56 with malonodinitrile bis-thiopyrano[2,3-d]thiazole derivative 58 was obtained, which early was synthesized in the reaction of 1,4-bis-(2,2′-dicyanovinyl)-benzene 57 with two equivalents of isorhodanine. In the second case, formation of the derivative 58 occured as two-stage process including an initial Michael reaction with further cyclization of the intermediate by the attack of cyano group with mercapto group of thiazole cycle (Scheme 17) [38]. Unexpectedely, Zhang and coauthors obtained thiopyranoid scaffold 60 (Scheme 18) exploring the divergent organocatalitic Michael-Michael-aldol cascade reaction of isorhodanine with α,βunsaturated aldehydes. Whilst the same conditions in the reaction of thiazolidinedione and rhodanine with enals led to spiro compounds, in the case of isorhodanine usage Michael cyclization took place. Optimizing the reaction conditions authors had used toluene medium and organic catalyst 59 at room temperature [44].

Synthesis of Polycondensed Thiopyrano[2,3-d]Thiazole Derivatives as Potentially Biological Active Compounds
The tandem and "domino" processes based on [4+2]-cycloaddition reaction is a powerful and effective tool in the synthesis of thiopyrano[2,3-d]thiazole derivatives. This type of reactions allows the synthesis of structurally complex molecules with high selectivity, while the consumption of solvents, reagents, adsorbents and energy is significantly reduced comparing with traditional multistage synthetic approaches. Moreover, most of the tandem and "domino" reactions products have drug-like structure and probably may possess interesting pharmacological effects that is important point in the modern process of drugs development.

Synthesis of Polycondensed Thiopyrano[2,3-d]Thiazole Derivatives as Potentially Biological Active Compounds
The tandem and "domino" processes based on [4+2]-cycloaddition reaction is a powerful and effective tool in the synthesis of thiopyrano[2,3-d]thiazole derivatives. This type of reactions allows the synthesis of structurally complex molecules with high selectivity, while the consumption of solvents, reagents, adsorbents and energy is significantly reduced comparing with traditional multistage synthetic approaches. Moreover, most of the tandem and "domino" reactions products have drug-like structure and probably may possess interesting pharmacological effects that is important point in the modern process of drugs development.
The tandem and "domino" processes based on [4+2]-cycloaddition reaction is a powerful and effective tool in the synthesis of thiopyrano[2,3-d]thiazole derivatives. This type of reactions allows the synthesis of structurally complex molecules with high selectivity, while the consumption of solvents, reagents, adsorbents and energy is significantly reduced comparing with traditional multistage synthetic approaches. Moreover, most of the tandem and "domino" reactions products have drug-like structure and probably may possess interesting pharmacological effects that is important point in the modern process of drugs development.

Domino Reactions as a Systematic Approach to the Synthesis of Fused Thiopyrano[2,3-d]Thiazoles
In addition to tandem reactions, domino reactions also play an important role in the synthesis of thiopyrano[2,3-d]thiazoles of complex structure. A domino reaction involves two or more transformations, which result in the formation of bonds (usually C-C bonds) and occur under the same reaction conditions without adding new reagents and/or catalysts. In this process the subsequent reactions take place as a consequence of the functionality formed in the previous step [52].

Domino Reactions as a Systematic Approach to the Synthesis of Fused Thiopyrano[2,3-d]Thiazoles
In addition to tandem reactions, domino reactions also play an important role in the synthesis of thiopyrano[2,3-d]thiazoles of complex structure. A domino reaction involves two or more transformations, which result in the formation of bonds (usually C-C bonds) and occur under the same reaction conditions without adding new reagents and/or catalysts. In this process the subsequent reactions take place as a consequence of the functionality formed in the previous step [52].

Biological Activity of Thiopyrano[2,3-d]Thiazole Derivatives
One of the efficient and freguently used directions of search for new active compounds is based on the principle of privileged structures annealing in the condensed systems. This approach involves combination of different heterocyclic pharmacophores in one molecule and can be successfully illustrated by thiopyrano [2,3-d]thiazoles. Taking into account that thiopyrano [2,3-d]thiazole derivatives are cyclic isosteric mimetics of 5-ene-4-thiazolidinones without typical Michael acceptors properties, the study of possible biological activity of these compounds is of great interest.

Biological Activity of Thiopyrano[2,3-d]Thiazole Derivatives
One of the efficient and freguently used directions of search for new active compounds is based on the principle of privileged structures annealing in the condensed systems. This approach involves combination of different heterocyclic pharmacophores in one molecule and can be successfully illustrated by thiopyrano [2,3-d]thiazoles. Taking into account that thiopyrano [2,3-d]thiazole derivatives are cyclic isosteric mimetics of 5-ene-4-thiazolidinones without typical Michael acceptors properties, the study of possible biological activity of these compounds is of great interest.
One of the promising and quite new directions of thiazolidinone derivative investigations is the search for potent anti-parasitic agents, namely compounds exhibiting antitrypanosomal activity. Trypanosomiasis belongs to the so called world's neglected diseases caused by Trypanosoma spp. [64]. Among spiro thiopyrano [2,3-d]thiazole 117 derivatives an active compound inhibiting growth of Trypanosoma brucei brucei and Trypanosoma brucei gambiense (the causative agent of African trypanosomiasis) with the IC 50 values of 0.26 µM and 0.42 µM, respectively, was identified [48]. Interesting is dual anti-leukemic (log GI 50 = −5.16, −5.59) and trypanocidal effects observed for thiopyranothiazole 118 bearing norbornane moiety that may be used for establishing molecular modes of action for this class of compounds ( Figure 8) [63]. antituberculosis activity (compound 98, Figure 5) and low acute toxicity [17]. High anticancer activity was identified in the row of 3,7-dithia-5,14-diazapenthacyclo[9.5.1.0 2,10 .0 4,8. 0 12,16 ]heptadecenes. The most active were the hit-compounds 114 and 115, herewith 114 selectively inhibited growth of leukemia cell lines CCRF-CEM (Log GI50 = −6.40) and SR (Log GI50 = −6.06) [16]. 7-Phenyl-2-oxo-7phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazole-6-carbaldehyde 116 showed high level of antimitotic activity against leukemia with mean GI50/TGI values 1.26/25.22 μM [31]. One of the promising and quite new directions of thiazolidinone derivative investigations is the search for potent anti-parasitic agents, namely compounds exhibiting antitrypanosomal activity. Trypanosomiasis belongs to the so called world's neglected diseases caused by Trypanosoma spp. [64]. Among spiro thiopyrano [2,3-d]thiazole 117 derivatives an active compound inhibiting growth of Trypanosoma brucei brucei and Trypanosoma brucei gambiense (the causative agent of African trypanosomiasis) with the IC50 values of 0.26 μM and 0.42 μM, respectively, was identified [48]. Interesting is dual anti-leukemic (log GI50 = −5.16, −5.59) and trypanocidal effects observed for thiopyranothiazole 118 bearing norbornane moiety that may be used for establishing molecular modes of action for this class of compounds ( Figure 8) [63]. Summarising all the above, fused thiopyranothiazoles can be used as a source for new antibacterial as well as antiviral agents. They also inhibited parasites growth. These results correlate with established anticancer profiles of the thiopyranothiazoles. Moreover, such fused heterocycles can be investigated as potent non-steroidal anti-inflammatory agents. Some structure-activity relationships are outlined in the Figure 9. One of the promising and quite new directions of thiazolidinone derivative investigations is the search for potent anti-parasitic agents, namely compounds exhibiting antitrypanosomal activity. Trypanosomiasis belongs to the so called world's neglected diseases caused by Trypanosoma spp. [64]. Among spiro thiopyrano [2,3-d]thiazole 117 derivatives an active compound inhibiting growth of Trypanosoma brucei brucei and Trypanosoma brucei gambiense (the causative agent of African trypanosomiasis) with the IC50 values of 0.26 μM and 0.42 μM, respectively, was identified [48]. Interesting is dual anti-leukemic (log GI50 = −5.16, −5.59) and trypanocidal effects observed for thiopyranothiazole 118 bearing norbornane moiety that may be used for establishing molecular modes of action for this class of compounds ( Figure 8) [63]. Summarising all the above, fused thiopyranothiazoles can be used as a source for new antibacterial as well as antiviral agents. They also inhibited parasites growth. These results correlate with established anticancer profiles of the thiopyranothiazoles. Moreover, such fused heterocycles can be investigated as potent non-steroidal anti-inflammatory agents. Some structure-activity relationships are outlined in the Figure 9. Summarising all the above, fused thiopyranothiazoles can be used as a source for new antibacterial as well as antiviral agents. They also inhibited parasites growth. These results correlate with established anticancer profiles of the thiopyranothiazoles. Moreover, such fused heterocycles can be investigated as potent non-steroidal anti-inflammatory agents. Some structure-activity relationships are outlined in the Figure 9.

Conclusions
The efficient approaches to the thiopyranothiazoles scaffolds synthesis are outlined in this review. One of the most studied synthetic protocol for thiopyranothiazoles is the hetero-Diels-Alder [4+2]-cycloaddition being rather fast and efficient method that yields good outcomes and stereoselectivity of the products. The tandem processes based on hetero-Diels-Alder and Michael

Conclusions
The efficient approaches to the thiopyranothiazoles scaffolds synthesis are outlined in this review. One of the most studied synthetic protocol for thiopyranothiazoles is the hetero-Diels-Alder [4+2]-cycloaddition being rather fast and efficient method that yields good outcomes and stereoselectivity of the products. The tandem processes based on hetero-Diels-Alder and Michael reactions used for the thiopirano[2,3-d]thiazoles synthesis have also been discussed. In contrast to the well discribed various synthetic routes of thiopyranothiazoles synthesis, biological activity of these derivatives have not been studied that much. Nevertheless, they are considered as 5-ene-4-thiazolidinone synthetic biomimetics that save pharmacological profile without revealing Michael acceptors properties. Among established biological activities of the thiopyrano[2,3-d]thiazole derivatives, the anti-inflammatory, antibacterial, anticancer as well as aniparasitic activities are the most prominent and need further in-depth studies. Considering all the above, the directed search for new drug-like molecules and possible chemotherapeutic agents among thiopyrano[2,3-d]thiazole derivatives is justified and promising direction in the medicinal chemistry. Moreover, the way of annealing of thiazolidine core into thiopyranothiazole analogs is used as one of the molecular optimization directions to decrease the toxicity and/or avoid the Michael acceptor properties as well.
Author Contributions: R.L. conceived and designed the review; O.R. and A.L. analyzed the literature data; R.L. and A.K. wrote the paper. All authors read and approved the final manuscript.