
==== Front
Beilstein J Org Chem
Beilstein J Org Chem
Beilstein Journal of Organic Chemistry
1860-5397
Beilstein-Institut Trakehner Str. 7-9, 60487 Frankfurt am Main, Germany

10.3762/bjoc.20.184
Full Research Paper
Chemistry
Organic Chemistry
O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization
Dil Kateryna V https://orcid.org/0000-0001-6659-6298
12
Palchykov Vitalii A https://orcid.org/0000-0003-3748-4566
palchikoff82@gmail.com
1§
Müller Thomas J J Associate Editor
1 Research Institute of Chemistry and Geology, Oles Honchar Dnipro National University, Nauky Av. 72, Dnipro, 49045, Ukraine https://ror.org/00qk1f078 https://www.isni.org/isni/0000000103681727
2 Enamine Ltd. (www.enamine.net), Winston Churchill Str. 78, Kyiv, 02094, Ukraine
§ Web: https://palchykovchem.vercel.app

2024
27 8 2024
20 21432151
10.3762/bjoc.20.18414 5 2024
13 8 2024
Copyright © 2024, Dil and Palchykov
2024
Dil and Palchykov
https://creativecommons.org/licenses/by/4.0/ This is an open access article licensed under the terms of the Beilstein-Institut Open Access License Agreement (https://www.beilstein-journals.org/bjoc/terms/terms), which is identical to the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0). The reuse of material under this license requires that the author(s), source and license are credited. Third-party material in this article could be subject to other licenses (typically indicated in the credit line), and in this case, users are required to obtain permission from the license holder to reuse the material.
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-2H-thiopyran-3(4H)-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 SO2-containing analogue of anticancer drug-candidate enastron (SO2 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.

dihydropyrimidinone/thione/selenone
green chemistry
in silico biological profile
multicomponent reaction (MCR)
thiopyrandioxide
This work was partially supported by the Ministry of Education and Science of Ukraine (project 0122U001220).All costs related to the publication of this open access article were entirely funded by the Beilstein-Institut.

This article is part of the thematic issue "Multicomponent reactions IV".
==== Body
pmcIntroduction

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 [1–11]. 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].

Scheme 1 The general Biginelli reaction (A) and examples of DHMP (B) and thiopyran-1,1-dioxide (C) containing drugs.

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 numerous 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 [1–28–9]. 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).

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).

Considering our constant interest in the development of methods for the synthesis of new S-heterocyclic systems we tried to combine the broad synthetic potential of Biginelli condensation and high reactivity β-ketosulfone 1 (dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide) in various condensation reactions [14–20]. It was also worth mentioning that the thiopyran-1,1-dioxide motif is presented in a number of biologically active compounds including important market drugs as antiglaucoma agent dorzolamide [21], diuretic/anticancer meticrane [22] and antiherpesvirus agent amenamevir (ASP-2151) [23] which was recently synthesized by Ugi-4CR [24] (Scheme 1C).

Results and Discussion

Reaction optimization

Over the past two decades more than 300 various catalytic systems have been proposed for Biginelli chemistry, e.g., simple inorganic and organic acids, metal salts, metal oxides, ionic liquids, phosphines, nanocatalysts, organocatalysts, ion exchange resins [1,4,9] or even visible light-driven methods [25–28].

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.

Table 1 Optimization of reaction.

	
	
Entry	Conditionsа	Isolated yield 2a + 2a’, %	Isomer ratio,
2a:2a’	
	
1	0.8 equiv NaI, 0.8 equiv TMSCl, MeCN, 22 °C, 4 h	traces	n.d.	
2	4 equiv TMSCl, DMF, 60 °C, 14 h	traces	n.d.	
3	4 equiv TMSCl, DMF, −20 °C, 5 days	23	2:1	
4	4 equiv TMSCl, DMF, 22 °C, 3 days	59	2:1.2	
5	4 equiv TMSCl, DMF/MeCN (1:1), 22 °C, 2 days	51	3:1	
6b	3 equiv TMSCl, DMF, 22 °C, 5 days	72	2:1	
7	3 equiv HСl, EtOH, 82 °C, 6 h	23	1:0	
8	10 mol % p-TsOH, MeOH, 82 °C, 36 h	35	1:0	
9	10 mol % CAN, EtOH, 82 °C, 18 h	32	1:0	
10	10 mol % SrCl2·6H2O, EtOH, 82 °C, 18 h	8	1:0	
11	10 mol % La(NO2)3·6H2O, solvent-free, 82 °С, 18 h	61	1:0	
12 c	10 mol % Yb(OTf) 3 , solvent-free, 140 °C, 6 h	65	1:0	
13c	AcOH, 110 °C, 14 h	68	1:0	
14	AcOH, 82 °C, 14 h	40	1:0	
15	AcOH, 110 °C, 4 h	71	1:0	
16 c	AcOH, 110 °C, 4 h	74	1:0	
17d	TFA, 110 °C, 14 h	45	1:0	
18c	AcOH, MW (300 W), 120 °С, 20 min	36	1:0	
aUnless specifically stated the ratio of ketosulfone/benzaldehyde/thiourea 1:1:1 (1 mmol scale); bketosulfone (1 mmol, 1 equiv), benzaldehyde (2 mmol, 2 equiv), thiourea (1 mmol, 1 equiv); cketosulfone (1 mmol, 1 equiv), benzaldehyde (1 mmol, 1 equiv), thiourea (1.2 mmol, 1.2 equiv); dketosulfone (1 mmol, 1 equiv), benzaldehyde (1 mmol, 1 equiv), thiourea (3 mmol, 3 equiv).

One of the most effective promoters for this type of reaction is TMSCl [29–31] and we also tried to involve TMSCl in our study (Table 1, entries 1–6), but in any case, we received a mixture of regioisomeric products 2a/2a’ (3:1 to 2:1) confirmed by 2D NMR spectroscopy (see Supporting Information File 1, Figures S1–S6). Classical conditions for Biginelli reaction (reflux in ethanolic HCl) gave only 23% yield (Table 1, entry 7). Reflux in alcoholic media in the presence of p-toluenesulfonic acid or CAN (ceric ammonium nitrate) was also not particularly successful (Table 1, entries 8 and 9, yield 32–35%). We subsequently explored a range of reaction conditions to improve overall yield and selectivity. We experimented with Lewis acids (Table 1, entries 10–12) to catalyze the reaction and observe low conversion with SrCl2. The reaction was significantly better with both La(NO2)3 and Yb(OTf)3 under solvent-free conditions (Table 1, entries 11 and 12, yield 61–65%). The most promising results were obtained by using simplest heating in acetic acid (Table 1, entries 13–16). After some playing with temperature, reaction time, and ratio of starting reagents we ultimately found conditions (AcOH, 110 oC, 4 h) suitable best for our chemistry and leading to the yield of the target product 2a 74% (Table 1, entry 16). 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/EDG-substituted 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 [33–35].

Scheme 2 Scope of the obtained Biginelli products 2a–q.

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 SO2-containing analogue 2r of potent anticancer drug enastron in 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.

Scheme 3 Synthesis of SO2-containing enastron analogue 2r.

The structures of the synthesized compounds 2a–r were confirmed by spectral data. The 1H NMR spectra of the obtained products are characterized by the following signals: aromatic ring protons (6.25–8.23 ppm), Ar–CH group proton singlet (5.13–5.44 ppm), broadened NH singlets (7.78–10.89 ppm), as well as the corresponding signals of successive 3 × CH2 groups of the sulfone fragment (2.18–3.34 ppm). Such a set of signals clearly corresponds to the heterocycles depicted above. Figure S8 (see Supporting Information File 1) shows 1H NMR spectra for Ph-substituted O,S,Se-DHPMs 2a,h,o. It can be seen from them that when going from oxygen to selenium (2h→2a→2o), the signals of both NH groups shift to down field (7.87/9.26→9.75/10.50→10.26/10.85 ppm) and become more equivalent (Δδ = 1.39→0.75→0.59 ppm accordingly). The key signal in the 13C NMR spectra is located in the regions 174.04–174.69 ppm (C=S), 151.44–151.86 ppm (C=O), and 170.15–170.91 ppm (C=Se) accordingly.

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-type thiazole synthesis for postmodification of product 2a. By employing 2-bromoacetophenone, bromomalononitrile and 2-bromo-1-tetralone we obtained condensed thiazoles 3–5 in 67–88% yields using slightly modified methods described [37–39]. We also applied desulfurization to obtain products 6 and 7 [40–41] (Scheme 4).

Scheme 4 Postmodification of the Biginelli product 2a.

While the Hantzsch thiazole synthesis is well documented from a synthetic and mechanistic point [42–43] and do not need discussion, more desulfurizations and oxidations of rare Biginelli products are discussed in Supporting Information File 1 using compound 2a as an example.

In silico evaluation of ADMET parameters and biological profile

We performed in silico screening of the biological properties of Biginelli products 2a–r and their postfunctionalized derivatives 3–7 using SwissADME (http://www.swissadme.ch) [44], ProTox 3.0 (https://tox-new.charite.de) [45], and MolPredictX (https://www.molpredictx.ufpb.br) [46] free online software. 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 [48–52]. The lipophilicity (estimated as log Po/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 Å2 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).

Figure 2 Distribution of compounds 2a–r, 3–7 (log P (y)–MW (x)) through LLAMA software. The chemical structure of a representative compound 2m is shown.

We then used the free online software ProTox 3.0 for computational toxicity assessment of the products as their LD50 values. The tested compounds mainly belong to the 4th class of acute oral toxicity with 300 < LD50 ≤ 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 SO2-containing analogue of the anticancer drug-candidate enastron (SO2 vs C=O), and we believe a multitude 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.

Supporting Information

File 1 Experimental procedures and characterization data of new compounds.

The authors are grateful to Enamine Ltd. (Kyiv, Ukraine) for NMR/HRMS support. The authors also thank Charite University of Medicine, Germany (Institute for Physiology, Structural Bioinformatics Group), Federal University of Paraíba, Brazil (Laboratory of Cheminformatics), University of Lausanne, Switzerland (SIB Swiss Institute of Bioinformatics), and the University of Leeds, UK (School of Chemistry) for free online cheminformatics software. V.A.P. would like to express special thanks to the Matsumae International Foundation for financial support for the presentation of this work at the 15th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-15, November 20–23, 2023, Kyoto, Japan). In addition, last but not least, we thank all brave defenders of Ukraine that made finalizing this work possible.

Data Availability

The data that supports the findings of this study is available from the corresponding author upon reasonable request.
==== Refs
1 Faizan S Roohi T F Raju R M Sivamani Y BR P K J Mol Struct 2023 1291 136020 10.1016/j.molstruc.2023.136020
2 Sánchez-Sancho F Escolano M Gaviña D Csáky A G Sánchez-Roselló M Díaz-Oltra S del Pozo C Pharmaceuticals 2022 15 8 948 10.3390/ph15080948 36015096
3 Marinescu M Molecules 2021 26 6022 10.3390/molecules26196022 34641566
4 Chopda L V Dave P N ChemistrySelect 2020 5 5552 5572 10.1002/slct.202000742
5 Costanzo P Nardi M Oliverio M Eur J Org Chem 2020 3954 3964 10.1002/ejoc.201901923
6 Mohammadi B Behbahani F K Mol Diversity 2018 22 405 446 10.1007/s11030-017-9806-z
7 Kaur R Chaudhary S Kumar K Gupta M K Rawal R K Eur J Med Chem 2017 132 108 134 10.1016/j.ejmech.2017.03.025 28342939
8 Nagarajaiah H Mukhopadhyay A Moorthy J N Tetrahedron Lett 2016 57 5135 5149 10.1016/j.tetlet.2016.09.047
9 Suresh Sandhu J S ARKIVOC 2012 i 66 133 10.3998/ark.5550190.0013.103
10 Matos L H S Masson F T Simeoni L A Homem-de-Mello M Eur J Med Chem 2018 143 1779 1789 10.1016/j.ejmech.2017.10.073 29133039
11 Palchykov V Manko N Finiuk N Pokhodylo N Ukr Biochem Zh 2022 94 64 74 10.15407/ubj94.01.064
12 Zhao Y Wu H Wang Z Wei Y Wang Z Tao L Sci China: Chem 2016 59 1541 1547 10.1007/s11426-016-0219-4
13 Abelman M M Smith S C James D R Tetrahedron Lett 2003 44 24 4559 4562 10.1016/s0040-4039(03)00985-7
14 Palchykov V A Dil K V Okovytyy S I J Chem Technol 2023 31 411 418 10.15421/jchemtech.v31i2.126304
15 Dil K V Kozyriev Y K Palchykov V A Chem Pap 2023 77 7249 7254 10.1007/s11696-023-03006-9
16 Pokhodylo N T Tupychak M A Palchykov V A Synth Commun 2020 50 1835 1844 10.1080/00397911.2020.1757113
17 Shyyka O Y Pokhodylo N T Palchykov V A Finiuk N S Stoika R S Obushak M D Chem Heterocycl Compd 2020 56 793 799 10.1007/s10593-020-02732-2
18 Kozirev E K Palchykov V A Chem Heterocycl Compd 2019 55 349 351 10.1007/s10593-019-02463-z
19 Chabanenko R M Mykolenko S Yu Kozirev E K Palchykov V A Synth Commun 2018 48 2198 2205 10.1080/00397911.2018.1486427
20 Palchykov V A Chabanenko R M Konshin V V Dotsenko V V Krivokolysko S G Chigorina E A Horak Y I Lytvyn R Z Vakhula A A Obushak M D New J Chem 2018 42 1403 1412 10.1039/c7nj03846a
21 Fekri S Rabiei A Hooshmandi S Nouri H Abtahi S-H Int Ophthalmol 2024 44 101 10.1007/s10792-024-03005-z 38376643
22 Wang Y Sharma A Ge F Chen P Yang Y Liu H Liu H Zhao C Mittal L Asthana S Front Oncol 2023 13 1157366 10.3389/fonc.2023.1157366 37274234
23 Kawashima M Watanabe D Fujio K Komazaki H J Dermatol 2023 50 311 318 10.1111/1346-8138.16608 36353762
24 Li X Zarganes-Tzitzikas T Kurpiewska K Dömling A Green Chem 2023 25 1322 1325 10.1039/d2gc04869h
25 Mohamadpour F Sci Rep 2023 13 10262 10.1038/s41598-023-37526-x 37355768
26 Mohamadpour F ACS Omega 2022 7 10 8429 8436 10.1021/acsomega.1c05808 35309418
27 Gadkari Y U Hatvate N T Takale B S Telvekar V N New J Chem 2020 44 8167 8170 10.1039/d0nj01351j
28 Devthade V Kamble G Ghugal S G Chikhalia K H Umare S S ChemistrySelect 2018 3 4009 4014 10.1002/slct.201800591
29 Zhu Y Pan Y Huang S Synth Commun 2004 34 17 3167 3174 10.1081/scc-200028607
30 Ryabukhin S V Plaskon A S Ostapchuk E N Volochnyuk D M Tolmachev A A Synthesis 2007 417 427 10.1055/s-2007-965881
31 Zhu Y-l Huang S-l Pan Y-j Eur J Org Chem 2005 11 2354 2367 10.1002/ejoc.200400845
32 Heravi M M Ghavidel M Heidari B Curr Org Synth 2016 13 569 600 10.2174/1570179413666151218202307
33 Fouda A M Assiri M A Ali T E Phosphorus, Sulfur Silicon Relat Elem 2020 195 324 330 10.1080/10426507.2019.1694023
34 Mohammadi B Behbahani F K Marandi G B Mirza B Phosphorus, Sulfur Silicon Relat Elem 2021 196 54 60 10.1080/10426507.2020.1800702
35 Chen P Tu M Tetrahedron Lett 2018 59 987 990 10.1016/j.tetlet.2018.01.070
36 Bouzina A Bouone Y O Sekiou O Aissaoui M Ouk T-S Djemel A Mansouri R Ibrahim-Ouali M Bouslama Z Aouf N-E RSC Adv 2023 13 19567 19584 10.1039/d3ra02904b 37388149
37 Nemr M T M Teleb M AboulMagd A M El-Naggar M E Gouda N Abdel-Ghany A A Elshaier Y A M M J Mol Struct 2023 1272 134216 10.1016/j.molstruc.2022.134216
38 Nagarajaiah H M Khazi I A Begum N S J Chem Sci 2015 127 467 479 10.1007/s12039-015-0797-y
39 Banothu J Khanapur M Basavoju S Bavantula R Narra M Abbagani S RSC Adv 2014 4 22866 22874 10.1039/c4ra02514h
40 Wang X-C Wei Y Da Y-X Zhang Z Quan Z-J Heterocycles 2011 83 2811 2822 10.3987/com-11-12351
41 Kim S S Choi B S Lee J H Lee K K Lee T H Kim Y H Shin H Synlett 2009 599 602 10.1055/s-0028-1087920
42 Ali S H Sayed A R Synth Commun 2021 51 670 700 10.1080/00397911.2020.1854787
43 Duc D X Chung N T Curr Org Synth 2022 19 702 730 10.2174/1570179419666220216122637 35170413
44 Daina A Michielin O Zoete V Sci Rep 2017 7 42717 10.1038/srep42717 28256516
45 Banerjee P Eckert A O Schrey A K Preissner R Nucleic Acids Res 2018 46 W1 W257 W263 10.1093/nar/gky318 29718510
46 Tullius Scotti M Herrera‐Acevedo C Barros de Menezes R P Martin H-J Muratov E N Ítalo de Souza Silva Á Faustino Albuquerque E Ferreira Calado L Coy‐Barrera E Scotti. L Mol Inf 2022 41 12 10.1002/minf.202200133 10.1002/minf.202200133
47 Guan L Yang H Cai Y Sun L Di P Li W Liu G Tang Y Med Chem Commun 2019 10 148 157 10.1039/c8md00472b
48 Lipinski C A Lombardo F Dominy B W Feeney P J Adv Drug Delivery Rev 2001 46 3 26 10.1016/s0169-409x(00)00129-0
49 Ghose A K Viswanadhan V N Wendoloski J J J Comb Chem 1999 1 55 68 10.1021/cc9800071 10746014
50 Veber D F Johnson S R Cheng H-Y Smith B R Ward K W Kopple K D J Med Chem 2002 45 2615 2623 10.1021/jm020017n 12036371
51 Egan W J Merz K M Baldwin J J J Med Chem 2000 43 3867 3877 10.1021/jm000292e 11052792
52 Muegge I Heald S L Brittelli D J Med Chem 2001 44 1841 1846 10.1021/jm015507e 11384230
53 Colomer I Empson C J Craven P Owen Z Doveston R G Churcher I Marsden S P Nelson A Chem Commun 2016 52 7209 7212 10.1039/c6cc03244c
