O,S,Se-containing Biginelli products based on cyclic β -ketosulfone and their postfunctionalization

A one-pot three-component Biginelli synthesis of dihydropyrimidinones/thiones/selenones via acetic acid or solvent-free Yb(OTf) 3 - catalyzed tandem reaction of β -ketosulfone (dihydro-2 H -thiopyran-3(4 H )-one-1,1-dioxide), an appropriate urea, and arylaldehyde has been developed. The reaction proceeds with high chemo-and regioselectivity to give diverse DHPMs in reasonable yields up to 95%. Moreover, an SO 2 -containing analogue of anticancer drug-candidate enastron (SO 2 vs C=O) was obtained by using the here reported method in gram scale. We also demonstrate the reactivity of the Biginelli product in various directions – synthesis of condensed thiazoles and tetrazoles. In silico assessment of ADMET parameters shows that most compounds meet the lead-likeness requirements. The biological profiles of new compounds demonstrate high probability levels of activity against the following pathogens/diseases: Candida albicans, Alphis gossypii, Tripomastigote Chagas, Tcruzi amastigota, Tcruzi epimastigota, Leishmania amazonensis, and Dengue larvicida.


Introduction
Multicomponent reactions (MCRs) are the key methodology to access valuable heterocycles for medicinal chemistry projects.The classical Biginelli reaction (1893) is an acid-catalyzed, three-component reaction between an aldehyde, β-ketoester, and urea that produces 3,4-dihydropyrimidin-2(1H)-ones, also known as DHPMs (Scheme 1A).This reaction is believed to be one of the most famous MCRs with >2000 papers published in the last 20 years (according to Scopus database).These MCRs allow the direct synthesis of known DHMP drugs such as monastrol, piperastrol, enastron, fluorastrol etc. (Scheme 1B) and dozens of highly bioactive compounds with anticancer, antihypertensive, antiinflammatory, antioxidant, antimicrobial, antifungal, antimalarial, antitubercular, antidiabetic, antifilarial, anti-Alzheimer, antiepileptics and other activities [1][2][3][4][5][6][7][8][9][10][11].The concept of "privileged structures" in medicinal chemistry highlights derivatives capable of interacting with multiple receptors or enzymes, making them ideal candidates for drug discovery.Dihydropyrimidinones (DHPMs) and their derivatives are particularly noteworthy within this category.Accordingly, their synthesis is of significant interest for organic and medicinal chemists.DHPMs are found in a variety of marine-sourced alkaloids, which are essential for creating biologically active natural products [10].Some of the DHPM derivatives are also known as functional polymers, adhesives, and fabric dyes [8,12].
In recent decades, the scope of the original Biginelli reaction shown in Scheme 1A was significantly extended by variation of the 1,3-dicarbonyl-containing building blocks.Many groups have elegantly demonstrated the synthetic versatility of numer-ous enolizable carbonyl components, including β-keto esters, cyclic/acyclic β-diketones, β-keto amides, coumarins, alicyclic ketones, β-ketophosphonates, α-nitroketones, curcumin, and barbituric acid derivatives [1,2,8,9].We analyzed a number of Biginelli-type products and publications and concluded that Se-containing DHPMs among the rarest examples and, in addition to this, ketosulfones have never been used as enolizable carbonyl component in this chemistry.To the best of our knowledge only one compound from the target group was published (2003) [13] before this work, however, without any spectral evidence (Figure 1).
We started our study from the optimization of the reaction conditions using β-ketosulfone 1, benzaldehyde and thiourea as model reaction.According to the literature, the reaction has been shown to work best and most efficiently under acidic conditions since such conditions enhance the selectivity, so various catalysts, mainly acidic, were tested for the model Biginelli reaction and the results are shown in Table 1.One of the most effective promoters for this type of reaction is TMSCl [29][30][31] and we also tried to involve TMSCl in our study (Table ).However, increasing acidity and using trifluoroacetic acid (Table 1, entry 17) did not improve the overall yield.We also tried microwave activation conditions since this is a known technique for reactions of this type [32], but unfortunately, we did not find any improvement in the yield (Table 1, entry 18).

Reaction scope
We then used optimized reaction conditions from Table 1, entry 16 (method A) and 12 (method B) to further explore the scope of the reaction (Scheme 2).By employing various EWG/EDGsubstituted benzaldehydes and urea/thiourea/selenourea we synthesized novel Biginelli products 2a-q with up to 95% yield.The use of selenourea has been shown to give low yields of products (up to 33%).In fact, we have thus expanded the range of available selenium-containing DHPMs in addition to the work of other authors [33][34][35].
We also attempted to replace urea/thiourea/selenourea with N-alkyl/aryl-substituted analogues, and aldehyde component switch to heteroaromatic (2-pyridinaldehyde) and aliphatic (iPrCHO, cinnamaldehyde).Unfortunately, we failed in both replacements and were unable to obtain any reasonable products.The list of unsuccessful reagents is shown in Figure S7 (see Supporting Information File 1).
Next, we paid attention to testing the conditions we developed for the synthesis of the SO 2 -containing analogue 2r of potent anticancer drug enastron gram scale (Scheme 3).Enastron is a novel dihydropyrimidine-based mitotic kinesin spindle protein KSP/Eg5 inhibitor [36].We hope that compound 2r and its analogues obtained in this work can be further deeply studied by in silico and in vitro methods to discover the compound most suitable for clinical trials.
The structures of the synthesized compounds 2a-r were confirmed by spectral data.The

Utilization of reaction products
The Biginelli reaction is the traditional method for synthesizing DHPM scaffolds, but it faces limitations in product diversity.
To overcome these challenges, two main strategies have been developed.The first strategy involves modifying the conventional components of the Biginelli chemistry, while the second focuses on the postmodification of the Biginelli products [2].Both approaches were tested in this work.We used Hantzsch-Scheme 2: Scope of the obtained Biginelli products 2a-q.
Considering ADMET [47] and other crucial properties, we found that all compounds (except for the nitro derivative 2e) do not violate the Lipinski, Ghose, Veber, Egan, and Muegge rules and PAINS filter [48][49][50][51][52].The lipophilicity (estimated as log P o/w ) for all compounds was shown to be in a wide range from 0.43 to 4.11.The topological polar surface area (TPSA), which is important for oral bioavailability, was found to be 67-129 Å 2 for all compounds except products 4 and 2e.None of the compounds penetrate the BBB (blood-brain barrier) except for seleno-2p and desulfurized product 7. Regarding water solubility, we can conclude that all compounds are either soluble or moderately soluble.For more details, see Supporting Information File 1 (Table S1).To visualize the lead-likeness of compounds 2a-r, 3-7, we utilized the free online software LLAMA (https://llama.leeds.ac.uk) [53], which showed that 70% of the products (16 of 23) fall within the specific lead-like space (Figure 2).
We then used the free online software ProTox 3.0 for computational toxicity assessment of the products as their LD 50 values.
The tested compounds mainly belong to the 4th class of acute oral toxicity with 300 < LD 50 ≤ 2000 mg/kg.In addition, we used MolPredictX (https://www.molpredictx.ufpb.br)[46] to evaluate potential biotargets (pathogens, species, diseases) for new synthesized compounds.If we focus on high levels of biological activity probability (80% and above), the following pathogens and diseases may be potential areas of interest: Alphis gossypii, Tripomastigote Chagas, Candida albicans, Tcruzi amastigota, Leishmania amazonensis, Tcruzi epimastigota, Dengue larvicida, and for selected cases Alzheimer and Sars-COVID.For more details, see Table S1 (Supporting Information File 1).

Conclusion
In summary, we have demonstrated the catalytic regioselective Biginelli synthesis of new S-heterocyclic systems -4-aryl-4,6,7,8-tetrahydro-1H-thiopyrano[3,2-d]pyrimidine-2(3H)-one/ thione/selenone 5,5-dioxides and some of their derivatives.Furthermore, this methodology was successfully applied for the synthesis of the SO 2 -containing analogue of the anticancer drug-candidate enastron (SO 2 vs C=O), and we believe a multi- tude of other sulfones of both synthetic and biological importance can be obtained by using the in this work reported efficient, multicomponent and green protocol.We postfunctionalized the typical Biginelli product using Hantzsch-type thiazole chemistry and desulfurization.Assessing drug-likeness, we found that most of the synthesized compounds correspond to the parameters established by the Lipinski, Ghose, Veber, Egan, and Muegge rules.In silico screening of their biological profiles indicated that these new derivatives fall into the 4th class of acute toxicity.Additionally, they exhibit potential high activity against diseases associated with these species: Alphis gossypii, Tripomastigote Chagas, Candida albicans, Tcruzi amastigota, Leishmania amazonensis, Tcruzi epimastigota, Dengue larvicida, and for selected cases Alzheimer and Sars-COVID.

Table 1 :
Optimization of reaction.

Figure 1: Number
of aryl-substituted Biginelli-type products and publications as analyzed by Reaxys database.The search was performed using depicted substructures "on all atoms" (May 2024).