Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2023 Jan 3;14(1):59–65. doi: 10.1021/acsmedchemlett.2c00425

Lipase-Catalyzed Synthesis and Biological Evaluation of N-Picolineamides as Trypanosoma cruzi Antiproliferative Agents

Fabricio Freije García †, Daniel Musikant ‡, José L Escalona ‡, Martín M Edreira ‡, Guadalupe García Liñares †,*
PMCID: PMC9841590  PMID: 36655123

Abstract

graphic file with name ml2c00425_0008.jpg

In our search for new safe antiparasitic agents, an enzymatic pathway was applied to synthesize a series of N-pyridinylmethyl amides derived from structurally different carboxylic acids. Thirty derivatives, including 11 new compounds, were prepared through lipase-catalyzed acylation in excellent yields. In order to optimize the synthetic methodology, the impact of different reaction parameters was analyzed. Some compounds were evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for American trypanosomiasis (Chagas’ disease). Some of them showed significant activity as parasite proliferation inhibitors. Amides derived from 2-aminopicoline and stearic and elaidic acids were as potent as nifurtimox against the amastigote form of T. cruzi, the clinically relevant form of the parasite. Even more, a powerful synergism between nifurtimox and N-(pyridin-2-ylmethyl)stereamide was observed, almost completely inhibiting the proliferation of the parasite. Besides, the obtained compounds showed no toxicity in Vero cells, making them excellent potential candidates as lead drugs.

Keywords: picoline derivatives, Chagas’ disease, lipase, enzymatic synthesis

Infections provoked by trypanosomatids are among the most prevalent parasitic diseases worldwide.1 In particular, Chagas disease, a life-threatening disease caused by Trypanosoma cruzi, represents a serious threat to the health of people living in poor populations in Latin America, where it is estimated that around 8 million people are infected and over 40 million individuals are at risk of infection.2,3 In developed countries, where Chagas’ disease is not endemic, the main transmission mechanism is via the placenta, migration of individuals, or by blood transfusion.4,5 Recently, it has been demonstrated that Chagas disease can be also transmitted sexually6 or by food ingestion.7

The current chemotherapy for Chagas’ disease is still deficient and is limited to two old and empirically discovered drugs, nifurtimox (1) and benznidazole (2) (Chart 1), that show unwanted and severe side effects, especially when used in the chronic phase of the disease.4,8−10 Even though in the last 50 years some compounds, mostly antifungals, have been studied in clinical trials without success,11−13 no new drugs have been developed to replace the current therapy. Therefore, there is an urgent need for the development of a safe and effective chemotherapy involving new antiparasitic drugs.14,15

Chart 1. Chemical Structure of Current Drugs Clinically Employed for the Treatment of Chagas’ Disease.

Chart 1

Open in a new tab

It is widely known that numerous compounds that contain an aromatic nitrogen heterocyclic ring are among the most significant structural components of approved pharmaceuticals.16 Particularly, pyridines,17 pyrimidines,18,19 and quinolines20−23 are interesting scaffolds for the development of new drugs. Specifically, pyridine, a simple six-membered heterocycle containing one nitrogen atom in the ring, is found in a variety of naturally occurring compounds and pharmaceutical compounds.24 Pyridine derivatives have been reported for a variety of biological properties, such as anticancer activity,25,26 antimicrobial activity,27 and antiviral activity.28 However, little has been reported about new compounds showing activity against T. cruzi.

Enzymes are interesting catalysts, which provide highly sustainable alternatives to conventional chemical methods,29−32 arising in the last years as efficient catalysts for synthesis under mild reaction conditions for a great scope of reactions, with high selectivity and large substrate specificity.33−35 Hydrolases constitute a class of enzymes, which catalyze either hydrolytic or reverse bond-formation reactions. Due to their easy handling to not needing a cofactor and their ability to perform in aqueous systems and in organic solvents, hydrolases have been incorporated into numerous synthetic routes, allowing the efficient production of alcohols, amines, esters, amides, epoxides, and nitriles, among other relevant molecules.36−39 This class of enzymes has been also industrially applied to the synthesis of, for example, pharmaceuticals, agrochemicals, and several high added-value substances.29,40,41

In the last years, lipases have been extensively used in nonaqueous media for a variety of organic transformations such as aminolysis, esterifications, polymerizations, etc.33,34,42−45 Using lipases, we have obtained diverse biologically active novel compounds from multiple substrates, with applications as potential antiparasitic,23,46,47 antitumoral,48 and antiviral agents.49,50

In this work, an enzymatic synthesis of N-pyridinylmethyl amides derived from structurally different carboxylic acids was performed to obtain a set of new compounds containing a pyridine ring (Chart 2). In recent years, much attention has been focused on this type of compound because many of them have interesting activities. In our ongoing research in the field of antiparasitic activity of organic compounds, we have also tested the title compounds as potential growth inhibitors of the protozoan T. cruzi.

Chart 2. Synthesized N-Pyridinylmethyl Amides.

Chart 2

Open in a new tab

The preparation of N-(pyridinylmethyl)amides has been reported in a variety of conditions, including direct coupling driven by carbodiimide51 or carbonyldiimidazole52 or the synthesis of 2-aminopicoline derivatives with oleic and linoleic acids in low yield. Dimethylaminopyridine-catalyzed acylation led to the acetylated derivative of 3-aminopicoline with 46% yield, and direct amidation in water is also reported, although the yield is not detailed.53,54 However, a biocatalytic approach to direct amidation has not been reported. In this paper, we report an enzymatic strategy for the preparation of a series of N-(pyridinylmethyl)amides from 2-, 3-, and 4-aminomethylpyridine and diverse structurally different carboxylic acids with short, medium, and long chains, saturated and unsaturated bonding patterns, cis and trans configurations, etc. (Scheme 1). The lipase-catalyzed amidation reported in the present work allows us to directly use carboxylic acid, bypassing intermediaries such as anhydrides or acyl chlorides. Through this process, the formation of undesired products is avoided, and the purification step is simplified. The use of a suitable solvent for a great scope of acids, the mild reaction conditions, and the possibility of reusing the catalyst constitute additional advantages.

Scheme 1. Preparation of 2-, 3-, and 4-Pyridinylmethyl Amino Derivatives.

Scheme 1

Open in a new tab

In the first place, a good combination of lipase and solvent, using 4-(aminomethyl)pyridine (4-AMP, 5) and ethyl acetate as acyl donor, was pursued. The conditions used for this step of the optimization were known to perform well in other amide syntheses: 30 °C, 200 rpm stirring, a 5.0 enzyme/substrate ratio (E/S, m/m), 5.0 acylating agent/substrate ratio (A/S, mol/mol), and a substrate concentration of 9.25 mM.49 The lipases tested were lipozyme from Rhizomucor miehei (RMIM), Lipase B from Candida antarctica (CAL B), and lipozyme from Thermomyces lanuginosus (TLIM). On account of the effect of solvents in lipase-catalyzed reactions being dependent on the type of substrate, it is difficult to predict.55 Therefore, to select a suitable solvent, screening experiments were carried out. n-Hexane, toluene, and diisopropyl ether (DIPE) were initially tested. As can be seen in Table 1, the three enzymes were active, and CAL B and TLIM were the ones that gave the most satisfactory results. The conversion percentage was determined at 72 h of reaction. The n-hexane, despite being an excellent solvent for other lipase-catalyzed reactions, was not a suitable solvent for this particular reaction (Table 1, entries 1, 4, and 7). Toluene led to an excellent conversion with CAL B (Table 1, entry 2), but it was no match for DIPE, which was the best solvent with all the enzymes (Table 1, entries 3, 6, and 9). In the absence of biocatalyst, no product was obtained. Based on these results, to continue analyzing the reaction conditions, we selected CAL B as biocatalyst and DIPE as solvent. We have also considered experimenting with cyclohexane and methyl-tert-butyl ether (MTBE), two solvents that have proven to be efficient in lipase-catalyzed condensations. However, conversion percentages were lower than with DIPE with values of 40% and 80%, respectively. Then, % conversion at different times (12, 18, and 24 h) was measured, and it was observed that the extent of the reaction at 24 h was similar to that at 72 h (Table 1, entries 10 and 11).

Table 1. Lipase-Catalyzed Synthesis of N-(4-Pyridinylmethyl)acetamide (9a).

entry enzyme solvent acyl donor E/S A/S T (°C) conv (%) reaction time (h)
1 CAL B n-hexane AcOEt 5 5 30   72
2 CAL B toluene AcOEt 5 5 30 94 72
3 CAL B DIPE AcOEt 5 5 30 96 72
4 RMIM n-hexane AcOEt 5 5 30   72
5 RMIM toluene AcOEt 5 5 30 39 72
6 RMIM DIPE AcOEt 5 5 30 57 72
7 TLIM n-hexane AcOEt 5 5 30   72
8 TLIM toluene AcOEt 5 5 30 54 72
9 TLIM DIPE AcOEt 5 5 30 95 72
10 CAL B DIPE AcOEt 5 5 30 95 24
11 TLIM DIPE AcOEt 5 5 30 92 24
12 CAL B DIPE AcOH 5 5 30 94 24
13 TLIM DIPE AcOH 5 5 30 19 24
14 CAL B DIPE AcOH 2 5 30 94 24
15 CAL B DIPE AcOH 1 5 30 92 24
16 CAL B DIPE AcOH 5 2 30 95 24
17 CAL B DIPE AcOH 5 1 30 95 24
18 CAL B DIPE AcOH 2 2 30 93 24
19 CAL B DIPE AcOH 1 1 30 86 24
20 CAL B DIPE AcOH 1 1 50 97 24
21 CAL B DIPE AcOH 1 1 60 100 12
Open in a new tab

Since we seek to optimize the direct amidation of fatty acids, we assayed for acetic acid as an acyl donor instead of ethyl acetate. Although acetic acid is strong enough to form an insoluble salt with the amine, the CAL B catalyzed amidation proceeds to the same extent as when ethyl acetate is used (Table 1, entries 12 and 13); a visual indicator of the end of the reaction is the disappearance of the precipitate. With TLIM, acetic acid did not work as a good acylating agent. Considering that CAL B gives better results than TLIM and acetic acid is a good acyl donor, we set these two conditions as optimal.

Once we established the best combination of enzyme and solvent, we aimed to search for the optimal E/S and A/S ratios. First, by keeping the A/S ratio constant, we decreased the amount of enzyme. It was observed that, with an E/S ratio of 1, the conversion was still excellent (Table 1, entry 15). Lowering that ratio even further, the conversion decreased significantly. Something similar occurred when we kept the E/S ratio constant and decreased the amount of acylating agent (Table 1, entries 16 and 17). Then, we decreased both ratios simultaneously, observing that, with E/S and A/S ratios of 1, the conversion, although it decreased, was still very good (Table 1, entries 18 and 19).

Because using smaller amounts of both enzyme and acylating agent is always more convenient, we choose E/S = 1 and A/S = 1 ratios, although the percentage conversion is slightly lower (Table 1, entry 19). Since a subsequent optimization in the reaction temperature could help to improve that yield, minimizing the waste of an amine excess, we have carried out the reaction at 50 and 60 °C, observing that the conversion is quantitative at 60 °C. Finally, we determined that, at this temperature, the reaction was complete after 12 h of reaction (Table 1, entry 21).

In summary, we have defined the best conditions found with CAL B as biocatalyst, DIPE as solvent, E/S and A/S of 1, and 60 °C.

Once we delineated the reaction conditions, we extrapolated them to acylate not only 4-AMP but also its positional isomers 3-(aminomethyl)pyridine (3-AMP, 4) and 2-(aminomethyl)pyridine (2-AMP, 3), with a variety of fatty acids (6a–6j). The conversion percentages were determined by 1H NMR of the crude reaction product at 12 h of reaction (Figure 1). All compounds were fully characterized through their 1H and 13C NMR and high-resolution mass spectrometry (HRMS) and the yield of isolated product for N-(pyridinylmethyl)amides 7–9, are detailed in Supporting Information.

Figure 1.

Figure 1

Open in a new tab

Conversion percentages for lipase-catalyzed acylation of aminomethylpyridines. Reaction conditions: biocatalyst: CAL B; solvent: DIPE; T = 60 °C; E/S = 1; A/S = 1; t = 12 h.

Following the progress of each reaction, no significant differences were observed in the lipase activity for the acylation of methylaminopyridines (3–5) with each carboxylic acid. In all cases, the yield was excellent with a slight favorable tendency for 2-aminomethylpyridine. For each aminopicoline, an increase was observed in the conversion increasing the chain length of the saturated fatty acid up to C14; then, conversion decreased again with the long chain (6a–6f) and unsaturations number (6f–6j). For acetic acid, yield maximum was achieved for all aminopicolines. The best performance was achieved with a chain of 14 carbon atoms (6d) since the respective products (7d–9d) were obtained in almost quantitative yield at 12 h of reaction. This effect has already been observed in the acylation of vanillylamine with TLIM as biocatalyst, with an intermediate chain favoring the reaction.49 It is interesting to note that the reaction with elaidic acid (6h) deviates from this tendency between unsaturated acids, probably due to the trans configuration.

To investigate a potential antitrypanosomal effect, the synthesized compounds were tested against intracellular stages of T. cruzi, the clinically more relevant forms of the parasite.56 Cytotoxicity of the synthesized compounds was tested on a Vero cell line at concentrations ranging from 10 to 600 μM, using the resazurin method. After 72 h of incubation at 37 °C, fluorescence was measured at 590 nm, and the CC50 (concentration that reduced the proliferation of cells by 50%) was determined (Figure 2). The N-acylpicolylamides derived from a shorter chain (less than 12 carbons) were the least cytotoxic compounds. Derivatives from saturated long-chain carboxylic acids (more than 16 C) presented intermediate or low cytotoxicity. Noteworthy, derivatives with elaidic acid (7–9g), a monounsaturated acid with 18 carbon atoms and trans configuration, showed very low cytotoxicity; nevertheless, the derivatives of unsaturated Z isomers acids (6h–6j) were the most cytotoxic.

Figure 2.

Figure 2

Open in a new tab

CC50 ± standard deviation of title compounds determined by rezasurin method in Vero cells.

A screening of compounds was made in a T. cruzi infection model. Vero cells were infected with fluorescent parasites of the Y strain (Y-GFP).57 After parasite removal, compounds were added to media in a concentration 10 times lower than their CC50. At 72 h postinfection, cells were lysed, and the fluorescence signal from parasites was measured (Figure 3a). Compounds 7f and 7g showed lower infection levels than nifurtimox-treated cells. In accordance, compounds 7f and 7g also showed a decrease in the percentage of infection and the number of amastigotes/100 cells (Figure 3). Considering the undesirable secondary effects on patients treated with nifurtimox or benznidazole,8−10 new drugs that replace these old therapies are desirable. However, another useful strategy would be decreasing the dose and effect of the current therapies by cotreatment with new drugs. To evaluate this possibility, cells were cotreated with nifurtimox (35 μM)/7f (20 μM) or nifurtimox (35 μM)/7g (40 μM). Interestingly, both cotreatments showed a significant reduction in the percentage of infected cells (IC), in comparison with nontreated control cells (Figures 3c and 4). More importantly, cotreatments were more efficient in reducing the number of amastigote/100 cells, with nifurtimox/7f showing a stronger synergic effect that almost abolished amastigote intercellular growth (Figures 3c and 4).

Figure 3.

Figure 3

Open in a new tab

(a) Screening antiparasitic of compounds in intracellular forms of T. cruzi. Infection percentage (b) and amastigote/100 cells (c) were determined for nifurtimox/7f and nifutimox/7g. *p < 0.05, ***p < 0.001 vs IC; # p < 0.05; ## p < 0.01; ### p < 0.001 (synergic effect).

Figure 4.

Figure 4

Open in a new tab

Representative images of treatments: infected control (i), 1 (ii), 7f (iii), 1 + 7f (iv), 7g (v), and 1 + 7g (vi).

These results confirm that compounds 7f and 7g have activity against T. cruzi amastigotes proliferation and that a cotreatment with nifurtimox could be a potential option to avoid secondary effects on patients.

Lastly, the half-maximal inhibitory concentration (IC50) for the most active compounds and for compound 7c as a negative control were measured. The obtained values (data shown in Supporting Information) showed an IC50 greater than 100 μM for compound 7c and values of 16.35 ± 4.41 μM for 7f and 47.65 ± 1.39 μM for 7g.

In conclusion, in this work we reported the enzymatic synthesis of 30 N-(pyridinylmethyl)amides, 11 of them new compounds (7g, 7i, 7j, 8d, 8e, 8f, 8g, 8j, 9e, 9g, 9j), by direct acylation of 2-, 3-, and 4-methylaminopyridine. The described enzymatic pathway constitutes an excellent alternative to synthesize N-fatty acylpicolines in comparison with traditional chemical methods previously reported, which have the disadvantage of using metallic catalysts or toxic reagents. The biocatalyst is biodegradable and, in consequence, more friendly to the environment. Besides, the enzyme is insoluble in the reaction medium, it is easily removed, and can be reused in additional reactions. In this case, among evaluated enzymes, lipase from Candida antarctica (CAL B) gave the best results and retained 80% activity after four reaction cycles. The N-(pyridinylmethyl)amides were obtained with excellent yields.

On the other hand, some compounds were evaluated against the amastigote form of T. cruzi. Amide derivatives of 2-methylaminopyridine with stearic acid (7f) and elaidic acid (7g), saturated and E isomer monounsaturated C18 fatty acids, respectively, were shown to be very effective inhibitors of T. cruzi intracellular proliferation exhibiting an efficacy comparable to that of nifurtimox, one of the drugs currently used for the treatment of the disease and used as a control in this work. In addition, a strong synergism between nifurtimox and 7f was observed, almost completely inhibiting the proliferation of amastigotes. This result is of great interest since the combination of compounds would allow the use of lower concentrations of the drug. Taking into account, furthermore, that 7f has cytotoxicity comparable to that of nifurtimox and that 7g is less cytotoxic than nifurtimox, these compounds offer excellent prospects as potential drugs for chemotherapy of American trypanosomiasis.

Acknowledgments

We thank UBA (UBACYT 20020170100167BA) and CONICET (PIP 11220170100420CO) for partial financial support.

Glossary

Abbreviations

CAL B

Lipase B from Candida antarctica

RMIM

Lipozyme from Rhizomucor miehei

TLIM

Lipozyme from Thermomyces lanuginosus

DIPE

diisopropylether

MTBE

methyl-tert-butyl ether

2-AMP

2-(aminomethyl)pyridine

3-AMP

3-(aminomethyl)pyridine

4-AMP

4-(aminomethyl)pyridine

NMR

nuclear magnetic resonance

HRMS

high-resolution mass spectrometry

CC50

concentration that reduced the proliferation of cells by 50%

IC50

half maximal inhibitory concentration.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00425.

  • Materials and methods, synthesis and spectral data for compounds 7–9, biological evaluation, and 1H and 13C NMR spectra of all compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ml2c00425_si_001.pdf (2.5MB, pdf)

References

  1. Urbina J. A. Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop 2010, 115 (1–2), 55–68. 10.1016/j.actatropica.2009.10.023. [DOI] [PubMed] [Google Scholar]
  2. Organization, W. H. Fourth WHO report on neglected tropical diseases ;WHO, 2017.
  3. Organization, W. H. Chagas disease (also known as American trypanosomiasis). Online at https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis) (accessed 2022-06-09).
  4. García Liñares G.; Ravaschino E. L.; Rodriguez J. B. Progresses in the Field of Drug Design to Combat Tropical Protozoan Parasitic Diseases. Curr. Med. Chem. 2006, 13, 335–360. 10.2174/092986706775476043. [DOI] [PubMed] [Google Scholar]
  5. Brenière S. F.; Waleckx E.; Aznar C.. Other forms of transmission. In American Trypanosomiasis Chagas Disease ;Elsevier, 2017; pp 561–578. [Google Scholar]
  6. Gomes C.; Almeida A. B.; Rosa A. C.; Araujo P. F.; Teixeira A. R. L. American trypanosomiasis and Chagas disease: Sexual transmission. Int. J. Infect Dis 2019, 81, 81–84. 10.1016/j.ijid.2019.01.021. [DOI] [PubMed] [Google Scholar]
  7. Shikanai-Yasuda M. A.; Carvalho N. B. Oral transmission of Chagas disease. Clin Infect Dis 2012, 54 (6), 845–52. 10.1093/cid/cir956. [DOI] [PubMed] [Google Scholar]
  8. Docampo R.; Moreno S. N. J.. Biochemistry of Trypanosoma cruzi. In American Trypanosomiasis Chagas Disease ;Elsevier, 2017; pp 371–400. [Google Scholar]
  9. Perez-Molina J. A.; Crespillo-Andujar C.; Bosch-Nicolau P.; Molina I. Trypanocidal treatment of Chagas disease. Enferm Infecc Microbiol Clin (Engl Ed) 2021, 39 (9), 458–470. 10.1016/j.eimc.2020.04.011. [DOI] [PubMed] [Google Scholar]
  10. Urbina J. A. Recent clinical trials for the etiological treatment of chronic chagas disease: advances, challenges and perspectives. J. Eukaryot Microbiol 2015, 62 (1), 149–56. 10.1111/jeu.12184. [DOI] [PubMed] [Google Scholar]
  11. Urbina J. A. The long road towards a safe and effective treatment of chronic Chagas disease. Lancet Infectious Diseases 2018, 18 (4), 363–365. 10.1016/S1473-3099(17)30535-2. [DOI] [PubMed] [Google Scholar]
  12. Molina I.; Salvador F.; Sanchez-Montalva A. The use of posaconazole against Chagas disease. Curr. Opin Infect Dis 2015, 28 (5), 397–407. 10.1097/QCO.0000000000000192. [DOI] [PubMed] [Google Scholar]
  13. Chatelain E. Chagas disease drug discovery: toward a new era. J. Biomol Screen 2015, 20 (1), 22–35. 10.1177/1087057114550585. [DOI] [PubMed] [Google Scholar]
  14. Villalta F.; Rachakonda G. Advances in preclinical approaches to Chagas disease drug discovery. Expert Opin Drug Discov 2019, 14 (11), 1161–1174. 10.1080/17460441.2019.1652593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Moraes C. B.; Franco C. H. Novel drug discovery for Chagas disease. Expert Opin Drug Discov 2016, 11 (5), 447–55. 10.1517/17460441.2016.1160883. [DOI] [PubMed] [Google Scholar]
  16. Vitaku E.; Smith D. T.; Njardarson J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 2014, 57 (24), 10257–74. 10.1021/jm501100b. [DOI] [PubMed] [Google Scholar]
  17. Prachayasittikul S.; Pingaew R.; Worachartcheewan A.; Sinthupoom N.; Prachayasittikul V.; Ruchirawat S.; Prachayasittikul V. Roles of Pyridine and Pyrimidine Derivatives as Privileged Scaffolds in Anticancer Agents. Mini Rev. Med. Chem. 2017, 17 (10), 869–901. 10.2174/1389557516666160923125801. [DOI] [PubMed] [Google Scholar]
  18. Ishwar Bhat K.; Kumar A.; Nisar M.; Kumar P. Synthesis, pharmacological and biological screening of some novel pyrimidine derivatives. Medicinal Chemistry Research 2014, 23 (7), 3458–3467. 10.1007/s00044-014-0914-3. [DOI] [Google Scholar]
  19. Schormann N.; Velu S. E.; Murugesan S.; Senkovich O.; Walker K.; Chenna B. C.; Shinkre B.; Desai A.; Chattopadhyay D. Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg. Med. Chem. 2010, 18 (11), 4056–66. 10.1016/j.bmc.2010.04.020. [DOI] [PubMed] [Google Scholar]
  20. Kumar S.; Bawa S.; Gupta H. Biological activities of quinoline derivatives. Mini Rev. Med. Chem. 2009, 9 (14), 1648–54. 10.2174/138955709791012247. [DOI] [PubMed] [Google Scholar]
  21. Musiol R. An overview of quinoline as a privileged scaffold in cancer drug discovery. Expert Opin Drug Discov 2017, 12 (6), 583–597. 10.1080/17460441.2017.1319357. [DOI] [PubMed] [Google Scholar]
  22. Chan-On W.; Huyen N. T. B.; Songtawee N.; Suwanjang W.; Prachayasittikul S.; Prachayasittikul V. Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing FoxM1 inhibition in cholangiocarcinoma cells. Drug Des Devel Ther 2015, 9, 2033–2047. 10.2147/DDDT.S79313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Chanquia S. N.; Larregui F.; Puente V.; Labriola C.; Lombardo E.; Garcia Linares G. Synthesis and biological evaluation of new quinoline derivatives as antileishmanial and antitrypanosomal agents. Bioorg Chem. 2019, 83, 526–534. 10.1016/j.bioorg.2018.10.053. [DOI] [PubMed] [Google Scholar]
  24. Altaf A. A.; Shahzad A.; Gul Z.; Rasool N.; Badshah A.; Lal B.; Khan E. A Review on the Medicinal Importance of Pyridine Derivatives. J. Drug Des. Med. Chem. 2015, 1, 1–11. 10.11648/j.jddmc.20150101.11. [DOI] [Google Scholar]
  25. Karki R.; Song C.; Kadayat T. M.; Magar T. B.; Bist G.; Shrestha A.; Na Y.; Kwon Y.; Lee E. S. Topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship study of dihydroxylated 2,6-diphenyl-4-aryl pyridines. Bioorg. Med. Chem. 2015, 23 (13), 3638–54. 10.1016/j.bmc.2015.04.002. [DOI] [PubMed] [Google Scholar]
  26. Kovala-Demertzi D.; Papageorgiou A.; Papathanasis L.; Alexandratos A.; Dalezis P.; Miller J. R.; Demertzis M. A. In vitro and in vivo antitumor activity of platinum(II) complexes with thiosemicarbazones derived from 2-formyl and 2-acetyl pyridine and containing ring incorporated at N(4)-position: synthesis, spectroscopic study and crystal structure of platinum(II) complexes with thiosemicarbazones, potential anticancer agents. Eur. J. Med. Chem. 2009, 44 (3), 1296–302. 10.1016/j.ejmech.2008.08.007. [DOI] [PubMed] [Google Scholar]
  27. Abdel-Megeed M. F.; Badr B. E.; Azaam M. M.; El-Hiti G. A. Synthesis, antimicrobial and anticancer activities of a novel series of diphenyl 1-(pyridin-3-yl)ethylphosphonates. Bioorg. Med. Chem. 2012, 20 (7), 2252–8. 10.1016/j.bmc.2012.02.015. [DOI] [PubMed] [Google Scholar]
  28. Schnute M. E.; Cudahy M. M.; Brideau R. J.; Homa F. L.; Hopkins T. A.; Knechtel M. L.; Oien N. L.; Pitts T. W.; Poorman R. A.; Wathen M. W.; Wieber J. L. 4-Oxo-4,7-dihydrothieno[2,3-b]pyridines as Non-Nucleoside Inhibitors of Human Cytomegalovirus and Related Herpesvirus Polymerases. J. Med. Chem. 2005, 48, 5794–5804. 10.1021/jm050162b. [DOI] [PubMed] [Google Scholar]
  29. Choi J. M.; Han S. S.; Kim H. S. Industrial applications of enzyme biocatalysis: Current status and future aspects. Biotechnol Adv. 2015, 33 (7), 1443–54. 10.1016/j.biotechadv.2015.02.014. [DOI] [PubMed] [Google Scholar]
  30. Drauz K.; Gröger H.; May O.. Enzyme Catalysis in Organic Synthesis ,3rd ed.; Wiley-VCH: Weinheim, Germany, 2012. [Google Scholar]
  31. Faber K.; Fessner W.-D.; Turner N. J.. Science of Synthesis: Biocatalysis in Organic Synthesis ,2nd ed.; Georg ThiemeVerlag: Stuttgart, Germany, 2015. [Google Scholar]
  32. Nestl B. M.; Hammer S. C.; Nebel B. A.; Hauer B. New generation of biocatalysts for organic synthesis. Angew. Chem., Int. Ed. Engl. 2014, 53 (12), 3070–95. 10.1002/anie.201302195. [DOI] [PubMed] [Google Scholar]
  33. Giri P.; Pagar A. D.; Patil M. D.; Yun H. Chemical modification of enzymes to improve biocatalytic performance. Biotechnol Adv. 2021, 53, 107868. 10.1016/j.biotechadv.2021.107868. [DOI] [PubMed] [Google Scholar]
  34. Fryszkowska A.; Devine P. N. Biocatalysis in drug discovery and development. Curr. Opin Chem. Biol. 2020, 55, 151–160. 10.1016/j.cbpa.2020.01.012. [DOI] [PubMed] [Google Scholar]
  35. Patel R. N.Pharmaceutical Intermediates by Biocatalysis: From Fundamental Science to Industrial Applications. In Applied Biocatalysis: From Fundamental Science to Industrial Applications ,1st ed.; Hilterhaus L., Liese A.; Kettling U., Antranikian G., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA, 2016; pp 367–403. [Google Scholar]
  36. Sandoval B. A.; Hyster T. K. Emerging strategies for expanding the toolbox of enzymes in biocatalysis. Curr. Opin Chem. Biol. 2020, 55, 45–51. 10.1016/j.cbpa.2019.12.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sheldon R. A.; Woodley J. M. Role of Biocatalysis in Sustainable Chemistry. Chem. Rev. 2018, 118 (2), 801–838. 10.1021/acs.chemrev.7b00203. [DOI] [PubMed] [Google Scholar]
  38. Adams J. P.; Brown M. J. B.; Diaz-Rodriguez A.; Lloyd R. C.; Roiban G. D. Biocatalysis: A Pharma Perspective. Advanced Synthesis & Catalysis 2019, 361, 2421–2432. 10.1002/adsc.201900424. [DOI] [Google Scholar]
  39. Patzold M.; Siebenhaller S.; Kara S.; Liese A.; Syldatk C.; Holtmann D. Deep Eutectic Solvents as Efficient Solvents in Biocatalysis. Trends Biotechnol 2019, 37 (9), 943–959. 10.1016/j.tibtech.2019.03.007. [DOI] [PubMed] [Google Scholar]
  40. Kumar A.; Singh S. Directed evolution: tailoring biocatalysts for industrial applications. Crit Rev. Biotechnol 2013, 33 (4), 365–78. 10.3109/07388551.2012.716810. [DOI] [PubMed] [Google Scholar]
  41. Bornscheuer U. T.; Kazlauskas R. J.. Hydrolases in Organic Synthesis: Regio- and Stereoselective Biotransformations ,2nd ed.; Wiley-VCH: Weinheim, Germany,2006. [Google Scholar]
  42. Winkler C. K.; Schrittwieser J. H.; Kroutil W. Power of Biocatalysis for Organic Synthesis. ACS Cent Sci. 2021, 7 (1), 55–71. 10.1021/acscentsci.0c01496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Whitthall J.; Sutton P. W.; Kroutil W.. Practical Methods for Biocatalysis and Biotransformations 3 ;John Wiley & Sons Ltd.: New York, 2016. [Google Scholar]
  44. Gotor V.; Alfonso I.; García-Urdiales E.. Asymmetric Organic Synthesis with Enzymes ;Wiley–VCH: Weinheim, Germany, 2008. [Google Scholar]
  45. García Liñares G.; Baldessari A. Lipases as Efficient Catalysts in the Synthesis of Monomers and Polymers with Biomedical Applications. Curr. Org. Chem. 2013, 17, 719–743. 10.2174/1385272811317070007. [DOI] [Google Scholar]
  46. García Liñares G.; Parraud G.; Labriola C.; Baldessari A. Chemoenzymatic synthesis and biological evaluation of 2- and 3-hydroxypyridine derivatives against Leishmania mexicana. Bioorg. Med. Chem. 2012, 20 (15), 4614–24. 10.1016/j.bmc.2012.06.028. [DOI] [PubMed] [Google Scholar]
  47. García Liñares G.; Antonela Zigolo M.; Simonetti L.; Longhi S. A.; Baldessari A. Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi. Bioorg. Med. Chem. 2015, 23 (15), 4804–4814. 10.1016/j.bmc.2015.05.035. [DOI] [PubMed] [Google Scholar]
  48. Quintana P. G.; García Liñares G.; Chanquia S. N.; Gorojod R. M.; Kotler M. L.; Baldessari A. Improved Enzymatic Procedure for the Synthesis of Anandamide andN-Fatty Acylalkanolamine Analogues: A Combination Strategy to Antitumor Activity. Eur. J. Org. Chem. 2016, 2016 (3), 518–528. 10.1002/ejoc.201501263. [DOI] [Google Scholar]
  49. Chanquia S. N.; Boscaro N.; Alché L.; Baldessari A.; Liñares G. G. An Efficient Lipase-Catalyzed Synthesis of Fatty Acid Derivatives of Vanillylamine with Antiherpetic Activity in Acyclovir-Resistant Strains. ChemistrySelect 2017, 2 (4), 1537–1543. 10.1002/slct.201700060. [DOI] [Google Scholar]
  50. Zigolo M. A.; Salinas M.; Alche L.; Baldessari A.; Linares G. G. Chemoenzymatic synthesis of new derivatives of glycyrrhetinic acid with antiviral activity. Molecular docking study. Bioorg Chem. 2018, 78, 210–219. 10.1016/j.bioorg.2018.03.018. [DOI] [PubMed] [Google Scholar]
  51. Braña M. F.; López Rodriguez M. L.; Garrido J.; Roldan C. M. Synthesis of N,N’-Diacyl-l,2-di-(4-pyridyl)ethylenediamine. J. Heterocyclic Chem. 1981, 18, 1305–1308. 10.1002/jhet.5570180707. [DOI] [Google Scholar]
  52. Wu H.; Kelley C. J.; Pino-Figueroa A.; Vu H. D.; Maher T. J. Macamides and their synthetic analogs: evaluation of in vitro FAAH inhibition. Bioorg. Med. Chem. 2013, 21 (17), 5188–97. 10.1016/j.bmc.2013.06.034. [DOI] [PubMed] [Google Scholar]
  53. Trova M. P.; Wissner A.; Carroll M. L.; Kerwar S. S.; Pickett W. C.; Schaub R. E.; Torley L. W.; Kohler C. A. Analogues of Platelet Activating Factor. 8. Antagonists of PAF Containing an Aromatic Ring Linked to a Pyridinium Ring. J. Med. Chem. 1993, 36, 580–590. 10.1021/jm00057a008. [DOI] [PubMed] [Google Scholar]
  54. Plater M. J.; Barnes P.; McDonald L. K.; Wallace S.; Archer N.; Gelbrich T.; Horton P. N.; Hursthouse M. B. Hidden signatures: new reagents for developing latent fingerprints. Org. Biomol Chem. 2009, 7 (8), 1633–41. 10.1039/b820257e. [DOI] [PubMed] [Google Scholar]
  55. Adlercreutz P.Fundamentals of Biocatalysis in Neat Organic Solvents. In Organic Synthesis with Enzymes in Non-Aqueous Media ;Wiley, 2008; pp 1–24. [Google Scholar]
  56. Zingales B.; Miles M. A.; Moraes C. B.; Luquetti A.; Guhl F.; Schijman A. G.; Ribeiro I. Drugs for Neglected Disease, I.; Chagas Clinical Research Platform, M., Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity. Mem Inst Oswaldo Cruz 2014, 109 (6), 828–33. 10.1590/0074-0276140156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Musikant D.; Leverrier A.; Bernal D.; Ferri G.; Palermo J. A.; Edreira M. M. Hybrids of Cinchona Alkaloids and Bile Acids as Antiparasitic Agents Against Trypanosoma cruzi. Molecules 2019, 24 (17), 3168. 10.3390/molecules24173168. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml2c00425_si_001.pdf (2.5MB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES