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Article

Easy Synthesis and In Vitro Evaluation of Halogenated Chalcones against Trypanosoma cruzi

by
Alcives Avila-Sorrosa
1,*,
Diana J. Laurel-Gochicoa
1,
María Elena Vargas-Díaz
1,
Benjamín Nogueda-Torres
2,* and
Rogelio I. Gómez-Escobedo
2
1
Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Departamento de Química Orgánica, Carpio y Plan de Ayala S/N, Santo Tomás, Ciudad de México 11340, Mexico
2
Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Departamento de Parasitología, Carpio y Plan de Ayala S/N, Santo Tomás, Ciudad de México 11340, Mexico
*
Authors to whom correspondence should be addressed.
Chemistry 2024, 6(5), 1201-1216; https://doi.org/10.3390/chemistry6050069
Submission received: 10 July 2024 / Revised: 23 September 2024 / Accepted: 24 September 2024 / Published: 9 October 2024
(This article belongs to the Section Medicinal Chemistry)
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Abstract

:
Chalcones are organic structures that occur naturally in flavonoids and isoflavonoids from diverse vegetables and fruits. Their properties have promising applications in medicinal chemistry as antiparasitic agents against malaria, leishmaniasis, and Chagas disease. Parasitic diseases, a global health challenge, affect thousands of people around the world. The lack of access to affordable treatments causes many deaths, especially in developing countries. Chagas disease, a neglected infection whose etiological agent is the protozoan Trypanosoma cruzi (T. cruzi), is currently incurable without timely treatment and depends on two primary nitrated chemotherapeutic agents: Nifurtimox (Nfx) and Benznidazole (Bzn). However, these drugs exhibit low selectivity and serious adverse effects, accentuating the critical need to develop new, safer chemotherapeutic options. In this context, herein we report the synthesis of halogen chalcone derivatives by an affordable and sustainable method. In vitro studies against T. cruzi demonstrated that the fluorine-containing structures have the best bioactive profile with inhibitions comparable to Nfx and Bzn. Additionally, ADME analysis was performed to determine the crucial physicochemical and pharmacokinetic descriptors of the series of compounds, which were shown to be suitable for enteral absorption and have a low risk of crossing the blood–brain barrier and damaging brain tissue.

1. Introduction

Nature is an unlimited source of multiple compounds that have inspired the development of a wide range of substances, medicines, and commodities that have improved the health and quality of life of people. Chalcones are organic structures related to flavonoids and isoflavones from various plants, fruits, and vegetables. They display broad pharmacological functions, such as antioxidant, anticonvulsant, antiplatelet, antimicrobial, antiparasitic, etc. (Figure 1) [1,2,3,4,5,6,7,8,9,10]. These compounds are of great interest in the development of new compounds with activity against different types of parasites that cause the so-called neglected diseases, including schistosomiasis [11], sleeping sickness [12], leishmaniasis [13], and Chagas disease [14,15]. This last illness unfortunately is a systemic parasitic infection that may be fatal without early treatment because its etiological agent, the hemoflagellate protozoan Trypanosoma cruzi (T. cruzi), invades vital tissues and organs, causing irreversible lesions that result in different clinical complications. Statistics indicate that between 6 and 7 million people suffer from this infection, bringing about 12,000 deaths annually. In addition, there are 75 million people at risk of infection with T. cruzi. The protozoan is frequently transmitted to humans through hematophagous triatomine insects (via vector) [16,17,18,19,20]. However, its infectious profile has varied, and it can be infected through blood transfusions, organ transplants, and laboratory accidents, as well as congenitally and orally (via non-vector) [21,22,23,24,25,26,27,28,29]. The infection presents two phases: acute and chronic. The first stage typically occurs 4 to 8 weeks after infection and is characterized by a high parasite count of T. cruzi (trypomastigotes stage) circulating in the bloodstream with mild symptoms and skin lesions. In the chronic phase, parasitemia in the bloodstream decreases, manifesting 2 to 3 months and even 30 years after the acute phase. Nevertheless, this stage has severe clinical complications, such as heart disease, megavisera, and central nervous system lesions, with fatal prognoses [30,31,32]. Chagas disease is treated mainly by two old-nitrated drugs: Nifurtimox (Nfx) and Benznidazole (Bzn) [33,34,35,36]. They can be effective mainly in the acute phase, with pediatric doses daily of Bzn from 5 to 10 mg/kg for 60 days for the case of ranging. Meanwhile, the Nfx doses are 15 mg/kg/day for 60 or 90 days. In adults, the recommended daily dose of Bnz is 5 mg/kg/day and 8 to 10 mg/kg/day for Nfx. Doses in the chronic phase may be variable depending on age, weight, tolerance, or clinical conditions such as allergies, and long-term treatments with Nfx and Bzn have contraindications in pregnancy, kidney or liver failure, and skin rashes [37,38,39,40]. Thus, T. cruzi is a protozoan resistant to chemotherapeutic agents and antibodies, and no vaccines prevent this infection. Licochalcone-A is a notable example of the antiparasitic potential of natural compounds against chloroquine-resistant strains of Plasmodium falciparum [41]. It also inhibits the growth of the promastigote form of Leishmania donovani [42]. Likewise, licochalcone-A, medicagenin, and other synthetic derivatives (Figure 1 and Figure 2) have shown effectiveness against T. cruzi, T. brucei, and Leishmania infantum. All of them contain phenolic groups (-OH) and methoxyl groups (-OCH3) that improve physicochemical properties, bioavailability, and biological activity, reducing cytotoxic effects on healthy cells [43,44,45]. The antiprotozoal activity of chalcones is due to their action on biological targets that are essential for the survival of the parasite. Among these targets, cruzin, a papain-like cysteine protease, is vital for the metabolic function and invasive proliferation of T. cruzi [46,47]. Some hydrazones-derived chalcones that include groups with the ability to establish hydrogen bonds (-NH2) have exhibited antiproliferative effect against T. cruzi and inhibition against the parasite enzyme (cruzain) with CL50 values between 20 and 60 μM [48]. Another promising example is the chalcone BNZTHP, which was effective against T. cruzi in the trypomastigotes stage, with a CL50 = 37.7 μM, being more potent than Bnz (CL50 = 161 μM) (Figure 2). Docking studies indicate affinity and high selectivity with cruzin, trypanothione reductase, and TcGAPDH enzymes [49]. Thus, it is a challenge to find bioactive molecules that are easily accessible and without adverse effects. Thus, parasitic diseases, a global health challenge, affect thousands of people around the world. The lack of access to affordable treatments causes many deaths, especially in developing countries. Our research focuses on designing cost-effective strategies to synthesize bioactive molecules, and some of them have shown effectiveness against T. cruzi, thanks to incorporating halogenated fractions that enhance their physicochemical properties and biological activity, applying green chemistry principles to improve its obtention, reduce costs, and minimize environmental impact [50,51,52,53,54,55]. Also, it found that incorporating more than two fluorine atoms increases cytotoxicity in healthy cells. Meanwhile, methoxyl groups (-OCH3) mitigate toxic effects and stabilize the α,β-unsaturated chalcone system by preventing Michael-type addition reactions [56,57]. The successful antimicrobial applications of natural chalcones with phenolic and methoxyl groups allow the synthesis of similar structures incorporating halogen to enhance their physicochemical properties and bioactivity without damaging normal cells.

2. Materials and Methods

2.1. Reagents and Apparatus

All reagents used were purchased from commercial sources and employed without prior purification. The solvents used were dried and distilled using procedures established before use [58]. Melting points were determined in triplicate in a capillary tube by a MEL-TEMP apparatus equipped with a mercury thermometer with a 0–400 °C scale. The vibrational IR spectroscopy was performed at 4000 to 450 cm−1, using a Bruker TENSOR 27 FT-IR spectrometer in a KBr tablet. Mass spectrometry analyses were performed by the electronic impact technique (IE-MS) and electrospray ionization (ESI-MS) operated at an ionization potential of 70 eV, using a JEOL JMS-SX102A spectrometer. NMR spectra were acquired in CDCl3 and DMSO-d6 at room temperature on a Bruker Advance III spectrometer with a frequency of 300 MHz for 1H, 75 Hz for 13C, and 283 Hz for 19F. Chemical shifts (δ) for 1H and 13C are reported in parts per million (ppm) downfield in relation to TMS, or the non-deuterated residual signal of the solvents, and in the case of the 19F, F3CCO2H was used as an external reference. The abbreviations used in the description of the NMR data are the following: s, singlet; d, doublet; dd, doublet of doublets; td, triplet doublets; m, multiplet. The coupling constants J are expressed in Hz. Elemental analyses were performed by a Thermo Scientific Flash 2000 elemental analyzer.

2.2. Synthesis of Halcone Derivatives (1–8)

The different derivatives of chalcones were synthesized by aldolic condensation reactions as indicated in the following procedure: to a solution of 1-(4-hydroxyphenyl) ethan-1-one (4.905 mmol) or 1-(3,4,5-trimethoxyphenyl) ethan-1-one in EtOH (10 mL), 2.5 mL of KOH (40%) (3.6 eq) was added and stirred for 10 min. Then, the corresponding benzaldehyde (4.905 mmol) in EtOH (5 mL) was added dropwise with stirring. The reaction mixture was kept stirred for 7 h at room temperature and monitored by thin-layer chromatography (mobile phase: hexane-ethyl acetate 7:3). After this time, hydrochloric acid was added until a pH = 5, giving a precipitate, which was filtered and washed with water (3 × 5 mL) and later with cold ether (2 × 3 mL).
(E)-1-(4-hydroxyphenyl)-3-phenylprop-2-en-1-one (1) [59].
Pale yellow solid (0.872 g, 3.89 mmol, 87%), mp 125–127 °C. IR (KBr), υ (cm−1): 3130, 1646, 1606, 1567, 1513, 1441, 1340, 1286, 1221, 1175, 1044, 980, 834, 766, 691, 675, 620, 560, 504, 482. ESI-MS, m/z: 225.11 (M.+ + 1). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.08 (d, J = 8.8 Hz, 2H, CH), 7.92 (d, J = 15.6 Hz, 1H, CH), 7.87–7.85 (m, 2H, CH), 7.68 (d, J = 15.6 Hz, 1H, CH), 7.46–7.42 (m, 3H, CH), 6.91 (d, J = 8.8 Hz, 2H, CH). 13C NMR (75 MHz, DMSO-d6), δ (ppm): 187.17, 162.33, 143.80, 134.92, 131.28, 130.39, 129.11, 128.95, 128.76, 122.11, 115.47. Anal. Cal. for C15H12O2 (224.26 g/mol): C, 80.34; H, 5.39; O, 14.27. Found: C, 80.11; H, 5.47; O, 14.20.
(E)-3-(4-chlorophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (2) [60].
Pale yellow solid (0.817 g, 3.16 mmol, 82%), mp 150–152 °C. IR (KBr), υ (cm−1): 3094, 3018, 2944, 1644, 1601, 1541, 1514, 1487, 1404, 1343, 1287, 1230, 1173, 1086, 1036, 980, 958, 845, 815, 742, 670, 635, 600, 532, 511, 493. ESI-MS, m/z: 257 (M.+ + 1, 35 Cl, 75%) 259 (M.+ + 1, 37 Cl, 35%). 1H NMR (300 MHz, DMSO-d6), δ (ppm):10.56 (s, 1H, OH), 8.12 (d, J = 8.7 Hz, 2H, CH), 7.97 (d, J = 15.6 Hz, 1H, CH), 7.94 (d, J = 8.5 Hz, 2H, CH), 7.70 (d, J = 15.6 Hz, 1H, CH), 7.54 (d, J = 8.0 Hz, 2H, CH), 6.96 (d, J = 8.1 Hz, 2H, CH). 13C NMR (75 MHz, DMSO-d6), δ (ppm): 187.03, 162.36, 141.20, 134.75, 133.88, 131.22, 130.37, 128.98, 128.85, 122.91, 115.42. Anal. Cal. for C15H11ClO2 (258.70 g/mol): C, 69.64; H, 4.29; O, 12.37. Found: C, 69.61; H, 4.34; O, 12.31.
(E)-3-(4-bromophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (3) [61].
Pale yellow solid (0.846 g, 2.80 mmol, 85%), mp 189–190 °C. IR (KBr), υ (cm−1): 3093, 2800, 1901.8, 1644, 1603, 1541, 1583.4, 1541.9, 1513, 1485, 1400, 1341, 1319, 1287, 1279, 1227, 1173, 1112, 1070, 1034, 1008, 980, 959, 844, 812, 787, 670, 636, 593, 531, 509, 489. ESI-MS, m/z: 301 (M.+, 79Br, 51%) 303 (M.+, 81Br, 49%). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 10.47 (s, 1H, OH), 8.08 (d, J = 8.6 Hz, 2H, CH), 7.95 (d, J = 15.8 Hz, 1H, CH), 7.83 (d, J = 8.3 Hz, 2H, CH), 7.67–762 (m, 3H, CH), 6.90 (d, J = 6.90 Hz, 2H, CH). 13C NMR (75 MHz, DMSO-d6), δ (ppm): 187.01, 162.37, 141.39, 134.23, 131.87, 131.32, 130.67, 129.00, 123.67, 122.91, 115.45. Anal. Cal. for C15H11BrO2 (303.16 g/mol): C, 59.43; H, 3.66; O, 10.56. Found: C, 59.18; H, 3.47; O, 10.48.
(E)-3-(4-fluorophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (4) [62].
Yellow solid (0.934 g, 3.55 mmol, 93%), mp 195–197 °C. IR (KBr), υ (cm−1): 3130, 1646, 1607, 1567, 1508, 1440, 1416, 1341, 1286, 1220, 1157, 1042, 987, 823, 750, 676, 637, 608, 539, 518. ESI-MS, m/z: 243 (M.+ + 1). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 10.55 (s, 1H, OH), 8.08 (d, J = 8.6 Hz, 2H, CH), 7.93 (m, 3H, CH), 7.68 (d, J = 15.6 Hz, 1H, CH), 7.28 (t, J = 8.9 Hz, 2H, CH), 6.90 (d, J = 8.7 Hz, 2H, CH). 13C NMR (75 MHz, DMSO-d6), δ (ppm): 187.11, 163.61 (d, J = 250.1 Hz), 162.28, 141.56, 131.62 (d, J = 3.2 Hz), 131.08 (d, J = 8.5 Hz), 129.12, 122.02, 115.94 (d, J = 21.6 Hz), 115.44. Anal. Cal. for C15H11FO2 (242.25 g/mol): C, 74.37; H, 4.58; O, 13.21. Found: C, 74.33; H, 4.46; O, 13.23.
(E)-1-(3,4,5-trimethoxyphenyl)-3-phenylprop-2-en-1-one (5) [63].
Light yellow solid (0.761 g, 2.55 mmol, 76%), mp 85–87 °C. IR (KBr), υ (cm−1): 3435, 3091, 2952, 2936, 2836, 2644, 1992, 1657, 1603, 1581, 1563, 1508, 1487, 1463, 1412, 1337, 1257, 1232, 1195, 1182, 1161, 1132, 1064, 1002, 935, 917, 848, 810, 782, 753, 727, 686, 672, 631, 615, 574, 541, 506, 488. ESI-MS, m/z: 299 (M.+ + 1). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 7.79 (s, 5H, CH), 7.73–7.55 (m, 1H, CH) 7.40–7.34 (m, 1H, CH), 3.87 (s, 6H, CH3), 3.80 (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6), δ (ppm): 188.07, 152.61, 143.87, 141.77, 132.88, 130.13, 128.52, 128.27, 121.33, 105.65, 60.19, 55.87. Anal. Cal. for C18H18O4 (298.33 g/mol): C, 72.47; H, 6.08; O, 21.45. Found: C, 72.39; H, 6.12; O, 21.41.
(E)-3-(4-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (6) [64].
Light yellow solid (0.761 g, 2.55 mmol, 76%), mp 115–117 °C. IR (KBr), υ (cm−1): 3435, 2954, 2938, 2838, 1656, 1603, 1581, 1566, 1508, 1490, 1463, 1414, 1339, 1259, 1233, 1198, 1180, 1162, 1132, 1090, 1067, 1002, 936, 848, 813, 783, 754, 731, 675, 645, 542, 492, 456, 427. ESI-MS, m/z: 333 (M.+ +1, 35 Cl, 75%) 335 (M.+ + 1, 37 Cl, 35%). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 7.98–7.94 (m, 3H, CH), 7.73 (d, J = 15.6 Hz, 1H, CH), 7.54 (d, J = 8.1 Hz, 2H, CH), 7.44 (s, 2H, CH), 7.42 (s, 2H, CH), 3.91 (s, 6H, CH3), 3.77 (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6), δ (ppm): 187.73, 152.90, 142.34, 142.08, 135.03, 133.66, 132.80, 130.64, 128.87, 122.58, 106.23, 60.17, 56.21. Anal. Cal. for C18H17ClO4 (332.78 g/mol): C, 64.97; H, 5.15; O, 19.23. Found: C, 64.88; H, 5.10; O, 19.26.
(E)-3-(4-bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (7) [65].
Light yellow solid (0.781 g, 2.07 mmol, 78%), mp 118–120 °C. IR (KBr), υ (cm−1): 3435, 3091, 2952, 2936, 2836, 2644, 1992, 1657, 1603, 1581, 1563, 1508, 1487, 1463, 1412,1337, 1257, 1232, 1195, 1182, 1161, 1132, 1064, 1002, 935, 917, 848, 810, 782, 753, 727, 686, 672, 631, 615, 574, 541, 506, 488. ESI-MS, m/z: 377 (M.+ + 1, 79Br, 51%), 379 (M.+ +1, 81Br, 49%). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 7.98 (d, J = 15.6 Hz, 1H, CH), 7.88 (d, J = 8.5 Hz, 2H, CH), 7.71 (d, J = 15.6 Hz, 1H, CH), 7.67 (d, J = 8.5 Hz, 2H, CH), 7.43 (s, 2H, CH), 3.90 (s, 6H, CH3), 3.77 (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6), δ (ppm): 187.74, 152.91, 142.45, 142.08, 133.99, 132.79, 131.80, 130.86, 123.91, 122.63, 106.23, 60.18, 56.22. Anal. Cal. for C18H17BrO4 (377.23 g/mol): C, 57.31; H, 4.54; O, 16.97. Found: C, 57.29; H, 4.52; O, 16.93.
(E)-3-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (8) [66].
Light yellow solid (0.677 g, 2.14 mmol, 70%), mp 113–115 °C. IR (KBr), υ (cm−1): 3062, 3014, 2971, 2941, 2834, 1661, 1611, 1599, 1583, 1507, 1465, 1449, 1415, 1341, 1247, 1229, 1193, 1178, 1159, 1127, 1096, 1069, 1002, 993, 934, 917, 866, 829, 819, 808, 776, 748, 735, 712, 692, 665, 575, 542, 524, 508, 486, 452, 416. ESI-MS, m/z: 317 (M.+ + 1). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 7.99 (dd, J = 8.7, 5.7 Hz, 2H, 2H, CH), 7.91 (d, J = 15.6 Hz, 1H, CH), 7.75 (d, J = 15.6 Hz, 1H, CH), 7.43 (s, 2H, CH), 7.31 (t, J = 8.8 Hz, 2H, CH), 3.90 (s, 6H, CH3), 3.77 (s, 3H, CH3). 13C NMR (75 MHz, DMSO), δ (ppm): 187.76, 163.37 (d, J = 248.9 Hz), 152.90, 147.83, 142.58, 142.01, 131.34 (d, J = 9.1, 5.8 Hz), 121.75 (d, J = 2.2 Hz), 115.85, (d, J = 21.8 Hz), 106.19, 65.16, 56.20. Anal. Cal. for C18H17FO4 (316.32 g/mol): C, 68.35; H, 5.42; O, 20.23. Found: C, 68.32; H, 5.37; O, 20.27.

2.3. Biological Assays

Derivatives of chalcones (1–8) were preliminarily evaluated in vitro in two Mexican strains of T. cruzi, NINOA and INC-5. Compounds and reference drugs, Nifurtimox (Nfx: Lampit, Bayer) and Benznidazole (Bnz: Rochagan, Roche), were dissolved at 10 mg/mL in dimethyl sulfoxide (DMSO, Sigma-Aldrich), and corresponding dilutions were carried out in phosphate-buffered saline (PBS). Bloodstream trypomastigotes of two strains of T. cruzi were used: NINOA strain (MHOM/MX/1994/NINOA, isolated from a patient in acute phase in Oaxaca, Mexico) and INC-5 strain (MHOM/MX/1994/INC5, isolated from a patient in chronic phase in Guanajuato, Mexico). CD1 mice 6–8 weeks old were intraperitoneally infected, at the maximum peak of parasitemia (4 weeks), and infected blood was obtained by cardiac puncture using heparin as an anticoagulant. Infected blood was adjusted to 1 × 106 parasites/mL and seeded into 96-well microplates. Animal experiments were performed according to Norma Oficial Mexicana (NOM-062-Z00–1999) [67]. The compounds were evaluated at different concentrations obtained by serial dilutions starting from 100 g/mL. In each well, 90 µL of infected blood and 10 µL of the corresponding compound or reference drug were deposited. A positive control of lysis reference drugs (Nfx and Bnz) was used, and DMSO 1% was used as the negative control. All assays were performed in triplicate. The microplate was incubated for 24 h at 4 °C. The quantification of bloodstream trypomastigotes was performed by the Brener-Pizzi method, 5 µL of blood was deposited between a slide and a coverslip (18 × 18 mm2), and all bloodstream trypomastigotes present in 20 fields were quantified in an optical microscope at 40x. The amount of trypomastigotes from each sample was compared to the negative control, and the percentage of lysis was determined. Finally, the lytic concentration of 50% parasites (LC50) was calculated for each compound and converted to micromolar data [68].

3. Results and Discussion

3.1. Synthesis

The structure of chalcones consists of two aromatic systems (A and B) connected by an α,β-unsaturated carbonyl, generating a highly conjugated 1,3-diarylprop-2-en-1-ones π-platform (chalconoid unit). There are various synthetic protocols for obtaining chalcones and derivatives, for example, the palladium-catalyzed cross-coupling reactions, the Friedel–Crafts reaction, the Julia–Kocienski olefination [69,70,71,72,73], and the Claisen–Schmidt aldol-condensation. The latter is one of the most straightforward methods to access chalcone derivatives under mild conditions using low-toxicity solvents in the reactions and the purification of the compounds [74,75]. Therefore, the synthesis of chalcone derivatives (1–8) was carried out employing an affordable method consisting of the condensation of para-hydroxyacetophenone, or 1-(3,4,5-trimethoxyphenyl)ethanone (ring A), with different para-substituted benzaldehydes (ring B), under mild conditions using 40% NaOH in EtOH at room temperature (Scheme 1). All compounds were obtained as yellow solids with melting points between 125 °C and 197 °C, with yields ranging from 65% to 80%. The synthesis strategy shows comparable and even better yields than those reported in the literature and exhibits high selectivity, giving the (E)-isomer exclusively [59,60,61,62,63,64,65,66].

3.2. Spectroscopic Characterization

All compounds were fully characterized using analytical and spectroscopic techniques, including FT-IR, NMR, mass spectrometry, and elemental analysis. These studies provide structural information about electronic and steric aspects related to their physical, chemical, and biological properties. The FT-IR spectra revealed the diagnostic bands of each chalcone derivative. Thus, signals CAr-H appear at ν 3100–3000 cm−1, and typical α,β-unsaturated carbonyl signal at ν 1680–1640 cm−1. Compounds 1–4 exhibit broad signals around ν 3300 cm−1 due to the hydroxyl groups, while the methoxylated 5–8 show two signals at ν 1310–1210 cm−1 and ν 1050–1000 cm−1, corresponding to the CAr-O and O-CH3 stretching, respectively. C-halogen signal appears at the interval ν 810–825 cm−1. In the case of mass spectrometry analysis (MS-ESI), all spectra showed the molecular ion plus one mass unit (M+ + 1), typical in this technique. As expected, halogenated derivatives 2, 3, 6, and 7 displayed the typical isotopic abundance of chlorine and bromine. The 1H NMR spectra showed all signals and chemical shifts characteristic for each type of hydrogen. Therefore, the aromatic signals are observed at the range δ 8.15 to δ 6.80 ppm and the broad band of -OH around δ 10.5 ppm. The protons of the double bond appear as doublets at δ 7.70 ppm and δ 7.95 ppm, assigned to alpha- and beta-hydrogen to carbonyl, respectively. Both signals exhibit a coupling constant of (J) of δ 15.5 Hz, confirming the selective synthesis of only the trans-isomer. For the hydroxylated derivatives (1–4), the aromatic signal is the most shifted to higher frequencies corresponding to the ortho-hydrogens to -OH, with multiplicities of doublet and J around 8 Hz. The aromatic signal shifted to lower frequencies (δ 8.15 ppm) corresponding to the ortho-hydrogens to the carbonyl group. Similarly, 13C NMR analysis showed aromatics signals between δ 105 and 170 ppm and observed the characteristic JC-F coupling around 250 Hz, and the carbonyl signal appears at lower frequencies approximately at 190 ppm. Methoxyl groups are observed to have higher frequencies at the range δ 50–60 ppm. Figure 3 and Figure 4 illustrate a representative example of 1H NMR and 13C NMR spectra of compound 8 and its different signals at typical chemical shifts (δ) [76]. All results of spectroscopic studies can be reviewed in the Supplementary Materials.

3.3. In Vitro Anti-Trypanosoma cruzi Assays

The trypomastigote stage of T. cruzi is the biologically infectious form in humans, characterized by high parasitemia in the bloodstream during the acute phase [77]. For this reason, susceptibility studies are crucial mainly in this stage of T. cruzi, for selecting bioactive compounds for treating Chagas disease. Therefore, compounds 1–8 were evaluated against two T. cruzi strains (NINOA and INC-5) (in vitro assay), employing Nfx and Bnz as standard drugs. The results indicate that both strains of T. cruzi are susceptible to different compounds (Table 1). In the case of the NINOA strain, compounds 1 and 7 displayed the lowest trypanocidal activity with around 20% of lysis, while compounds 3 and 5 were about 45%. Similarly, 6 showed a lysis percentage of 41%, while the chlorinated derivative 2 had a value of 61%. The highest activity against this strain was presented by fluorinated derivatives 4 and 8, with 75% and 72%, respectively, comparable to Bnz (79%) and about 15% less active than Nfx (91%). The susceptibility of the INC-5 strain revealed that chlorinated 6 and brominated compound 7 are the least active, with 37% and 25% of lysis, respectively. Compounds 1, 4, and 5 had lysis of around 55%, and the fluorinated derivative 3 was slightly higher, with 60%. Structures 2 and 8 were effective with approximately 70% of lysis, comparable to Bnz (74%) and very close to Nfx (80%). The susceptibility results demonstrate the high bioactivity of fluorinated compounds 4 and 8 in the NINOA strain, comparable to Bzn and close to Nfx. This is a promising finding that suggests the potential of these compounds against T. cruzi. Notably, the non-halogenated compound 1, despite having the lowest percentage of lysis, shows potential for improvement, indicating that fluorine and methoxyl groups could enhance its bioactive profile. The most active compounds, INC-5, correspond to derivatives 2, 3, and 8, with compound 2 showing comparable activity to the reference drugs. These results encouraged further studies to explore the biological potency of the series of compounds obtained.

Determination of CL50 agaist T. cruzi

In view of the promising susceptibility results of the halogenated compounds against both strains of T. cruzi, complementary studies were encouraged to determine the in vitro LC50 of each compound (Table 2). Hence, the trials displayed that in the NINOA strain, compounds 3, 5, and 7 had moderate potency with LC50 between 400 μM and 710 μM, far away from the references Nfx (161 μM) and Bzn (220 μM). Likewise, 4 had LC50 = 390 μM and 8 with a LC50 = 300 μM, respectively. Compounds 2 and 6 had a CL50 value of 120 μM and 100 μM, better than the reference drugs and twice as active as Bnz. Surprisingly, compound 1 showed the best LC50 value (30 µM), with a five- and seven-fold higher trypanocidal activity than Nfx and Bnz, respectively. In the case of the INC-5 strain, curiously, structure 1 was the least active with an LC50 = 510 µM, being the least active against this strain, which shows a better selectivity to the T. cruzi NINOA strain. Chlorinated structure 2 showed an LC50 = 330 µM, as did the brominated compound 7 (310 µM), whose values are comparable to the Bzn (310 µM). While 3 and 4 were more active than both reference drugs, they displayed LC50 values of 220 µM and 205 190 µM, respectively. Trimethoxylated compound 5 had LC50 = 260 µM comparable to Bnz. Analogous fluorinated 8 exhibited LC50 = 140 µM, with higher bioactivity than Bnz (310 µM) and approximately two times more active than Nfx (250 µM). Chlorinated compound 6 was the most active on the INC-5 strain, with a notable LC50 = 40 µM. The results showed an interesting tendency of chlorinated and fluorinated compounds to confer the most promising bioactivity against T. cruzi. These structural characteristics may be pertinent to the modulation of the chemistry of chalcone derivatives and their pharmacokinetic and pharmacodynamic parameters to improve the bioactive profile against T. cruzi. In summary, in the following order, compounds 1, 2, and 6 showed the highest trypanocidal profile in the NINOA strain, and compounds 6 and 8 had higher potency against the INC-5 strain. These assays suggest that the hydroxylated and methoxylated structures at ring A and chlorine and fluorine atoms at ring B of the chalcones structures are the most favorable to continue studying this class of compounds and optimize their structures in search of more effective and safe treatment for Chagas disease.

3.4. ADME Analysis

Drug design, discovery, and synthesis have experienced important advances through computational tools that allow estimating different physical and chemical properties that have a decisive impact on the pharmacodynamics and pharmacokinetics of bioactive compounds. These tools will enable the process of obtaining a new medicine to be improved and more efficient [78,79,80]. Oral administration of drugs is the most comfortable, economical, and safe option; therefore, the pharmacokinetic processes involved, such as adsorption, distribution, metabolism, and elimination (ADME), are crucial in searching for new drugs. Thus, oral administration implies adequate absorption through the gastrointestinal tract and appropriate distribution in the body to reach its site of action, which implies that the drug must have a slow metabolic degradation. Moreover, its elimination must be performed without any complication or damage to the organism. These pharmacokinetic steps are intimately related to the structural and physicochemical characteristics of the compounds; for this reason, it is of great interest to consider them in molecules with pharmacological applications. The ADME profile of the different halogenated structures was evaluated online using free programs available through the Swiss ADME servers (http://www.swissadme.ch/index.php, accessed on 1 January 2024) and pkCSM-pharmacokinetics (http://biosig.unimelb.edu.au/pkcsm/, accessed on 1 January 2024) by entering the corresponding SMILES of each molecular structure. Table 3 summarizes the most relevant physicochemical and pharmacokinetic properties of the computer-assisted analysis of the online tools. The SwissADME program determined Lipinski rule parameters without finding a violation in any of them. Therefore, log P of 1–8 was obtained from the consensus Po/w displays values between 3.17 and 3.97, being moderately lipophilic (log P < 5). Water solubility is obtained from the descriptor Log Sw (SILICOS-IT), with values ranging from −5.92 to −4.38, indicating a moderate solubility; only 7 (−6.13) has low solubility. The bioavailability radar provides meaningful information on optimal oral bioavailability values. The physicochemical properties of lipophilicity, size, polarity, solubility, flexibility, and saturation are considered. The appropriate values for these parameters are delimited by a pink zone that considers the following intervals: MW between 150 and 500 g/mol, polarity: TPSA between 20 and 130 Å2, solubility: log Sw < 6, saturation: sp3 carbon fraction, not less than 0.25, and flexibility: maximum 9 rotary bonds [81,82]. All pharmacokinetic and pharmacodynamic profiles of the different compounds can be reviewed in the Supplementary Materials.
In the case of 1, which presented the best bioactivity against the T. cruzi NINOA strain (CL50 = 30), it fully complies with the different parameters of the Lipinski rule (Figure 5). However, in the case of the bioavailability radar, only the saturation descriptor (INSAT) presents a value of 0.0, which is below the appropriate range. This same trend and INSAT value were present in the rest of the hydroxylated chalcones 2, 3, and 4. Unlike compounds 5 and 6, where the best bioavailability profiles were predicted, for example, in the case of the chlorinated compound 6 (Figure 6), which was the most active in the INC-5 strain (CL50 = 30), it shows values within the optimal ranges of all physicochemical descriptors, as well as a bioavailability radar practically within the optimally demarcated area, predicting good oral bioavailability like the other methoxylated derivatives 7 and 8. The descriptors of human intestinal absorption (HIA), total clearance (CLtot), the blood–brain barrier (BBB), and lethal dose values (LD50) (rats) were predicted using the pkCSM-pharmacokinetics tool. HIA values obtained for the series of compounds are between 92% and 98%; thus, the compounds with percentages less than 30% indicate poor absorption, while those greater than 80% present a high absorption profile.

4. Conclusions

A series of chalcone derivatives (1–8) were synthesized by an affordable method under mild reaction conditions. The spectroscopic analyses were consistent with the proposed molecular structures. In vitro assays against two T. cruzi strains (NINOA and INC-5), including Nfx and Bzn as reference drugs, indicated that in the case of NINOA, derivatives fluorinated 4 and 8 presented the better biological activity with 75% and 72%, respectively, being comparable to Bnz (79%) and 20% less than Nfx (91%). Similarly, the results on the INC-5 strain indicated that structures 8 and 2 displayed the most active inhibitory profile with 70% comparable to Bzn (73%) and close to Nfx (80%). The LD50 trial studies indicate that compounds 1, 2, and 6 have the highest potency against the NINOA strain, while 6 and 8 exhibit a higher bioactive profile on the INC-5 strain. Complementary ADME studies demonstrated that most compounds meet the parameters and physicochemical descriptors suitable for oral administration. Regarding the lethal dose values (LD50) in rats, they were estimated between 2.129 and 2.407 mg/kg. The blood–brain barrier (BBB) parameter indicated a moderate diffusion of the compounds toward the brain, indicating a low risk of damage to this nervous tissue. Thus, the in vitro and in silico studies of the different chalcone derivatives allow us to continue optimizing the most promising derivatives and perform complementary in vivo studies of cytotoxicity and selectivity in the future, seeking to improve the effectiveness and safety of these compounds as potential chemotherapies for Chagas disease.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/chemistry6050069/s1, Figure S1: 1H NMR (300 MHz; DMSO-d6) of compound 1; Figure S2: 13C NMR (75 MHz, DMSO-d6) of compound 1; Figure S3: Mass spectrometry (ESI) of compound 1; Figure S4: In silico pharmacokinetic and bioavailability profile of compound 1 (SwissADME); Figure S5: 1H NMR (300 MHz; DMSO-d6) of compound 2; Figure S6: 13C NMR (75 MHz, DMSO-d6) of compound 2; Figure S7: Mass spectrometry (ESI) of compound 2; Figure S8: In silico pharmacokinetic and bioavailability profile of compound 2 (SwissADME); Figure S9: 1H NMR (300 MHz, CDCl3) of compound 3; Figure S10: 13C NMR (75 MHz, CDCl3) of compound 3; Figure S11: Mass spectrometry (EI) of compound 3; Figure S12: In silico pharmacokinetic and bioavailability profile of compound 3 (SwissADME); Figure S13: 1H NMR (300 MHz, CDCl3) of compound 4; Figure S14: 13C NMR (75 MHz, CDCl3) of compound 4; Figure S15: Mass spectrum (ESI) of compound 4; Figure S16: In silico pharmacokinetic and bioavailability profile of compound 4 (SwissADME); Figure S17: 1H NMR (300 MHz; DMSO-d6) of compound 5; Figure S18: 13C NMR (75 MHz, DMSO-d6) of compound 5; Figure S19: Mass spectrum (EI) of compound 5; Figure S20: In silico pharmacokinetic and bioavailability profile of compound 5 (SwissADME); Figure S21: 13C NMR (300 MHz; DMSO-d6) of compound 6; Figure S22: 13C NMR (75 MHz, DMSO-d6) of compound 6; Figure S23: Mass spectrum (EI) of compound 6; Figure S24: In silico pharmacokinetic and bioavailability profile of compound 6 (SwissADME); Figure S25: 1H NMR (300 MHz; CDCl3) of compound 7; Figure S26: 13C NMR (75 MHz; CDCl3) of compound 7; Figure S27: Mass spectrum (EI) of compound 7; Figure S28: In silico pharmacokinetic and bioavailability profile of compound 7 (SwissADME); Figure S29: FT-IR (KBr) spectrum of compound 8; Figure S30: 1H NMR (300 MHz; CDCl3) of compound 8; Figure S31. 13C NMR (75 MHz; CDCl3) of compound 8; Figure S32: Mass spectrum (ESI) of compound 8; Figure S33: In silico pharmacokinetic and bioavailability profile of compound 8 (SwissADME).

Author Contributions

Conceptualization, A.A.-S.; methodology, A.A.-S., D.J.L.-G., B.N.-T., and R.I.G.-E.; software, A.A.-S.; validation, A.A.-S., M.E.V.-D., B.N.-T., R.I.G.-E., and D.J.L.-G.; formal analysis, A.A.-S., M.E.V.-D., and B.N.-T.; investigation, A.A.-S., M.E.V.-D., D.J.L.-G., B.N.-T., and R.I.G.-E.; resources, A.A.-S. and B.N.-T.; original draft preparation, A.A.-S.; writing—review and editing, A.A.-S. and B.N.-T.; supervision, A.A.-S. and B.N.-T.; project administration, A.A.-S.; funding acquisition, A.A.-S. and B.N.-T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by CONHACYT 167248, SIP-IPN (grants 20200028, 20210889, 20221698 and 20230942).

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding author/s.

Acknowledgments

A.A.-S.: and D.J.L.-G. would like to acknowledge Programa de Beca de Estímulo Institutional de Formación de Investigadores (BEIFI-IPN; 20200028, 20221698). Thanks to Nogueda-Torres and research group for his valuable collaboration and friendship.

Conflicts of Interest

The authors declare no conflicts of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Chemistry 06 00069 g001
Figure 1. Natural chalcones and their multiple bioactive functions.
Figure 1. Natural chalcones and their multiple bioactive functions.
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Figure 2. Synthetic chalcones with biological activity including antiprotozoal.
Figure 2. Synthetic chalcones with biological activity including antiprotozoal.
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Scheme 1. Synthesis of chalcones (1–8) by aldol-condensation reactions.
Scheme 1. Synthesis of chalcones (1–8) by aldol-condensation reactions.
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Figure 3. 1H NMR spectrum (300 MHz; DMSO-d6) of compound 8.
Figure 3. 1H NMR spectrum (300 MHz; DMSO-d6) of compound 8.
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Figure 4. 13 C NMR (75 MHz; DMSO-d6) of compound 8.
Figure 4. 13 C NMR (75 MHz; DMSO-d6) of compound 8.
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Figure 5. Pharmacokinetic and bioavailability profile of compound 1 (SwissADME).
Figure 5. Pharmacokinetic and bioavailability profile of compound 1 (SwissADME).
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Figure 6. Pharmacokinetic profile and bioavailability of compound 6 (SwissADME).
Figure 6. Pharmacokinetic profile and bioavailability of compound 6 (SwissADME).
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Table 1. Susceptibility tests of 1–8 against T. cruzi NINOA and INC-5.
Table 1. Susceptibility tests of 1–8 against T. cruzi NINOA and INC-5.
Compound% Lysis T. cruzi NINOA% Lysis T. cruzi INC-5
122.03 ± 0.5853.85 ± 0.00
261.02 ± 0.5873.08 ± 1.15
347.46 ± 0.5860.00 ± 1.15
475.42 ± 0.5856.15 ± 1.00
545.76 ± 1.1556.15 ± 0.00
641.53 ± 1.0036.92 ± 2.08
718.64 ± 2.6525.38 ± 0.58
872.03 ± 0.0068.46 ± 1.53
Bnz77.92 ± 1.1573.81 ± 1.53
Nfx90.91 ± 1.1579.76 ± 1.15
Results are expressed as the mean ± standard deviation.
Table 2. LC50 of chalcone derivatives (1–8) against NINOA and INC-5 strains.
Table 2. LC50 of chalcone derivatives (1–8) against NINOA and INC-5 strains.
CompoundCL50 (μM) Bloodstream Trypomastigotes T. cruzi
T. cruzi NINOAT. cruzi INC-5
130 ± 0.58510 ± 1.00
2120 ± 1.53330 ± 1.15
3470± 0.58220 ± 0.58
4390 ± 0.00190 ± 1.00
5710 ± 1.53260 ± 0.58
6100 ± 0.0040 ± 0.58
7660 ± 1.00310 ± 0.58
8300 ± 0.58140 ± 0.58
Bnz220 ± 1.00310 ± 1.00
Nfx161 ± 1.00250 ± 1.00
Results are expressed as the mean ± standard deviation.
Table 3. ADME in silico study of structures 1–8.
Table 3. ADME in silico study of structures 1–8.
Comp.MW
(g/mol)		Log PHaHdRbLog SwLipinski
Rule		HIA (%)BBBFuhTclLD50 Rat
(mol/kg)
1224.253.45213−4.38094.0460.1650.020.1492.129
2258.703.41213−5.00092.6370.1390.013−0.1762.335
3303.153.48213−5.22092.5700.1370.008−0.1982.347
4242.253.17313−4.66093.7060.0120.0580.0362.228
5298.333.34406−5.33097.9690.0530.00.2322.218
6332.783.88406−5.92096.5610.0260.00.3692.393
7377.233.97406−6.13096.4940.0250.00.3482.407
8316.323.67506−5.60097.629−0.10.0530.1192.405
Ha = bond acceptors; Hb = H-bond donors; Rb = rotatable bonds.
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MDPI and ACS Style

Avila-Sorrosa, A.; Laurel-Gochicoa, D.J.; Vargas-Díaz, M.E.; Nogueda-Torres, B.; Gómez-Escobedo, R.I. Easy Synthesis and In Vitro Evaluation of Halogenated Chalcones against Trypanosoma cruzi. Chemistry 2024, 6, 1201-1216. https://doi.org/10.3390/chemistry6050069

AMA Style

Avila-Sorrosa A, Laurel-Gochicoa DJ, Vargas-Díaz ME, Nogueda-Torres B, Gómez-Escobedo RI. Easy Synthesis and In Vitro Evaluation of Halogenated Chalcones against Trypanosoma cruzi. Chemistry. 2024; 6(5):1201-1216. https://doi.org/10.3390/chemistry6050069

Chicago/Turabian Style

Avila-Sorrosa, Alcives, Diana J. Laurel-Gochicoa, María Elena Vargas-Díaz, Benjamín Nogueda-Torres, and Rogelio I. Gómez-Escobedo. 2024. "Easy Synthesis and In Vitro Evaluation of Halogenated Chalcones against Trypanosoma cruzi" Chemistry 6, no. 5: 1201-1216. https://doi.org/10.3390/chemistry6050069

APA Style

Avila-Sorrosa, A., Laurel-Gochicoa, D. J., Vargas-Díaz, M. E., Nogueda-Torres, B., & Gómez-Escobedo, R. I. (2024). Easy Synthesis and In Vitro Evaluation of Halogenated Chalcones against Trypanosoma cruzi. Chemistry, 6(5), 1201-1216. https://doi.org/10.3390/chemistry6050069

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