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Chalcones are direct precursors in the biosynthesis of flavonoids. They have an α,ß-unsaturated carbonyl system which gives them broad biological properties. Among the biological properties exerted by chalcones, their ability to suppress tumors stands out, in addition to their low toxicity. In this perspective, the present work explores the role of natural and synthetic chalcones and their anticancer activity in vitro reported in the last four years from 2019 to 2023. Moreover, we carried out a partial least square (PLS) analysis of the biologic data reported for colon adenocarcinoma lineage HCT-116. Information was obtained from the Web of Science database. Our in silico analysis identified that the presence of polar radicals such as hydroxyl and methoxyl contributed to the anticancer activity of chalcones derivatives. We hope that the data presented in this work will help researchers to develop effective drugs to inhibit colon adenocarcinoma in future works.
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Adenocarcinoma , Antineoplásicos , Chalconas , Neoplasias del Colon , Humanos , Chalconas/farmacología , Neoplasias del Colon/tratamiento farmacológico , Flavonoides/farmacología , Antineoplásicos/farmacologíaRESUMEN
Leishmaniasis is an infectious disease with several limitations regarding treatment schemes. This work reports the anti-Leishmania activity of spiroacridine compounds against the promastigote (IC50 = 1.1 to 6.0 µg / mL) and amastigote forms of the best compounds (EC50 = 4.9 and 0.9 µg / mL) inLeishmania (L.) infantumand proposes an in-silico study with possible selective therapeutic targets for L. infantum. The substituted dimethyl-amine compound (AMTAC 11) showed the best leishmanicidal activity in vitro, and was found to interact with TryRandLdTopoI. comparisons with standard inhibitors were performed, and its main interactions were elucidated. Based on the biological assessment and the structure-activity relationship study, the spiroacridine compounds appear to be promisinganti-leishmaniachemotherapeutic agents to be explored.
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Acridinas/farmacología , Compuestos de Espiro/farmacología , Tripanocidas/farmacología , Acridinas/síntesis química , Acridinas/metabolismo , Acridinas/toxicidad , ADN-Topoisomerasas de Tipo I/metabolismo , Eritrocitos/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , NADH NADPH Oxidorreductasas/metabolismo , Pruebas de Sensibilidad Parasitaria , Unión Proteica , Proteínas Protozoarias/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/metabolismo , Compuestos de Espiro/toxicidad , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/metabolismo , Tripanocidas/toxicidadRESUMEN
Nine new spiroacridine derivatives were synthetized by introducing cyano-N-acylhydrazone group between the acridine and phenyl-substituted rings followed by spontaneous cyclization. The new compounds were assayed for their DNA binding properties, human topoisomerase IIα inhibition and bovine serum albumin (BSA) interaction. Besides, docking analysis were performed in order to better understanding the biomolecule-compounds interactions. All compounds interacted with BSA which was demonstrated by the fluorescence suppression constant of 104â¯M-1. Compounds with chloro and NO2 substituents at that para-position on phenyl ring demonstrated the best results for BSA interaction. DNA binding constant determined by UV-vis data demonstrated high values for AMTAC-11 and AMTAC-14, 1.1â¯×â¯108â¯M-1 and 4.8â¯×â¯106â¯M-1, respectively, and all others presented constant values of 105â¯M-1. AMTAC-06 with chloro at para-position on phenyl ring presented a topoisomerase II inhibition of 84.34% in comparison to the positive controls used. Docking studies indicated that AMTAC-06 is able to intercalate the DNA base pairs at topoisomerase IIα active site, preventing DNA connection after break, in a process known as poisoning. Topoisomerase enzyme inhibition result was correlated to BSA interaction profile, since AMTAC-06 showed the best results in both analysis. The findings obtained here proved that methoxy or chloro substitution on phenyl ring at para-position is fundamental for in vitro activity of new spiroacridine derivatives, and indicates that AMTAC-06 is a promising entity and should serve as a lead compound in the development of new DNA and protein binders, as well as human topoisomerase II inhibitors.
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Acridinas/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , ADN/química , Albúmina Sérica Bovina/química , Inhibidores de Topoisomerasa II/farmacología , Acridinas/síntesis química , Acridinas/química , Animales , Bovinos , Relación Dosis-Respuesta a Droga , Fluorescencia , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Perkinsus protozoan parasites have been associated with high mortality of bivalves worldwide, including Brazil. The use of antiproliferative drugs to treat the Perkinsosis is an unusual prophylactic strategy. However, because of their environment impact it could be used to control parasite proliferation in closed system, such as hatchery. This study evaluated the anti-Perkinsus activity potential of synthesized and commercial compounds. Viability of hypnospores of Perkinsus spp. was assessed in vitro. Cells were incubated with three 2-amino-thiophene (6AMD, 6CN, 5CN) and one acylhydrazone derivatives (AMZ-DCL), at the concentrations of 31.25; 62.5; 125; 250 and 500⯵M and one commercial chlorinated phenoxy phenol derivative, triclosan (2, 5, 10 and 20⯵M), for 24-48â¯h. Two synthetic molecules (6CN and AMZ-DCL) caused a significant decline (38 and 39%, respectively) in hypnospores viability, at the highest concentration (500⯵M), after 48â¯h. Triclosan was the most cytotoxic compound, causing 100% of mortality at 20⯵M after 24â¯h and at 10⯵M after 48â¯h. Cytotoxic effects of the compounds 6CN, AMZ-DCL, and triclosan were investigated by measuring parasite's zoosporulation, morphological changes and metabolic activities (esterase activity, production of reactive oxygen species and lipid content). Results showed that zoosporulation occurred in few cell. Triclosan caused changes in the morphology of hypnospores. The 6CN and AMZ-DCL did not alter the metabolic activities studied whilst Triclosan significantly increased the production of reactive oxygen species and changed the amount and distribution of lipids in the hypnospores. These results suggest that three compounds had potential to be used as antiprotozoal drugs, although further investigation of their mechanism of action must be enlightened.
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Alveolados/efectos de los fármacos , Antiprotozoarios/farmacología , Ostreidae/parasitología , Alveolados/patogenicidad , Alveolados/fisiología , Análisis de Varianza , Animales , Antiprotozoarios/uso terapéutico , Acuicultura , Bivalvos/parasitología , Brasil , Carboxilesterasa/efectos de los fármacos , Carboxilesterasa/metabolismo , Estuarios , Proteínas Fluorescentes Verdes , Hidrazonas/química , Hidrazonas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Sustancias Luminiscentes , Especies Reactivas de Oxígeno/metabolismo , Agua de Mar , Esporas Protozoarias/efectos de los fármacos , Tiofenos/química , Tiofenos/farmacología , Triclosán/farmacologíaRESUMEN
In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a-h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10(4) to 1.0 × 10(6) M(-1) and quenching constants from -0.2 × 10(4) to 2.18 × 10(4) M(-1) indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties.
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Acridinas/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Tiosemicarbazonas/química , Antineoplásicos/farmacología , ADN/química , Células MCF-7RESUMEN
Four new nitrogen-containing heterocyclic derivatives (acridine, quinoline, indole, pyridine) were synthesized and their biological properties were evaluated. The compounds showed affinity for DNA and HSA, with CAIC and CAAC displaying higher binding constants (Kb) of 9.54 × 104 and 1.06 × 106, respectively. The fluorescence quenching assay (Ksv) revealed suppression values ranging from 0.34 to 0.64 × 103 M-1 for ethidium bromide (EB) and 0.1 to 0.34 × 103 M-1 for acridine orange (AO). Molecular docking confirmed the competition of the derivatives with intercalation probes at the same binding site. At 10 µM concentrations, the derivatives inhibited topoisomerase IIα activity. In the antiproliferative assays, the compounds demonstrated activity against MCF-7 and T47-D tumor cells and nonhemolytic profile. Regarding toxicity, no acute effects were observed in the embryos. However, some compounds caused enzymatic and cardiac changes, particularly the CAIC, which increased SOD activity and altered heart rate compared to the control. These findings suggest potential antitumor action of the derivatives and indicate that substituting the acridine core with different cores does not interfere with their interaction and topoisomerase inhibition. Further investigations are required to assess possible toxicological effects, including reactive oxygen species generation.
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Antineoplásicos , Inhibidores de Topoisomerasa , Inhibidores de Topoisomerasa/farmacología , Inhibidores de Topoisomerasa/química , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Antineoplásicos/química , ADN/química , Sustancias Intercalantes/farmacología , Acridinas/farmacología , Acridinas/química , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Estructura MolecularRESUMEN
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), responsible for generating COVID-19, has spread worldwide and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020, being responsible for various damages to public health, social life, and the economy of countries. Its high infectivity and mutation rates have stimulated researchers and pharmaceutical companies to search for new therapies against this disease. These efforts resulted in several vaccines and the identification of Molnupiravir as an oral treatment for this disease. However, identifying new alternatives and critical information is necessary to fight against this devastating agent. The findings in recent years regarding the structure and biochemistry of SARS-CoV2 are remarkable. In anti-CoV drug discovery, various targets, such as structural, non-structural, and hostrelated proteins are explored. In fact, 3CLpro is the most used among non-structural proteins since this protease cleaves peptide sequences after the glutamine residue, and no human protease has this function. This makes this macromolecule an excellent drug target for discovering new compounds. Another promising target is the transmembrane protease serine 2 (TMPRSS2). Recent studies point to TMPRSS2 as one of the main targets responsible for viral entry related to the cleavage of the S protein. Similar to cathepsins, TMPRSS2 is also responsible for cleaving the spike protein SARS-CoV2, which binds to the ACE2 receptor. Thus, TMPRSS2 is one of the targets that may represent new alternatives in treating SARS-CoV2. In this context, would discovering a multitarget inhibitor be the new strategy in searching for drugs against SARS-CoV2? For many years, new drug discovery was based on the "one drug, one target" premise, where the biological action is related to interactions with only one biological target. However, this paradigm has been overcome as new evidence of multiple mechanisms of action for a single drug. Finally, this review will present a perspective on drug design based on a multitarget strategy against 3CLpro and TMPRSS2. We hope to provide new horizons for researchers worldwide searching for more effective drugs against this devastating agent.
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COVID-19 , SARS-CoV-2 , Humanos , ARN Viral , Descubrimiento de Drogas , Serina Endopeptidasas/farmacologíaRESUMEN
Neglected tropical diseases (NTDs) constitute a group of approximately 20 infectious diseases that mainly affect the impoverished population without basic sanitation in tropical countries. These diseases are responsible for many deaths worldwide, costing billions of dollars in public health investment to treat and control these infections. Among them are the diseases caused by protozoa of the Trypanosomatid family, which constitute Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (sleeping sickness), and Leishmaniasis. In addition, there is a classification of other diseases, called the big three, AIDS, tuberculosis, and malaria, which are endemic in countries with tropical conditions. Despite the high mortality rates, there is still a gap in the treatment. The drugs have a high incidence of side effects and protozoan resistance, justifying the investment in developing new alternatives. In fact, the Target-Based Drug Design (TBDD) approach is responsible for identifying several promising compounds, and among the targets explored through this approach, N-myristoyltransferase (NMT) stands out. It is an enzyme related to the co-translational myristoylation of N-terminal glycine in various peptides. The myristoylation process is a co-translation that occurs after removing the initiator methionine. This process regulates the assembly of protein complexes and stability, which justifies its potential as a drug target. In order to propose NMT as a potential target for parasitic diseases, this review will address the entire structure and function of this enzyme and the primary studies demonstrating its promising potential against Leishmaniasis, T. cruzi, T. brucei, and malaria. We hope our information can help researchers worldwide search for potential drugs against these diseases that have been threatening the health of the world's population.
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Enfermedad de Chagas , Leishmaniasis , Malaria , Parásitos , Animales , Humanos , Aciltransferasas , Enfermedad de Chagas/tratamiento farmacológico , Leishmaniasis/tratamiento farmacológico , Enfermedades Desatendidas/tratamiento farmacológicoRESUMEN
The concept of "one target, one drug, one disease" is not always true, as compounds with previously described therapeutic applications can be useful to treat other maladies. For example, acridine derivatives have several potential therapeutic applications. In this way, identifying new potential targets for available drugs is crucial for the rational management of diseases. Computational methodologies are interesting tools in this field, as they use rational and direct methods. Thus, this study focused on identifying other rational targets for acridine derivatives by employing inverse virtual screening (IVS). This analysis revealed that chitinase enzymes can be potential targets for these compounds. Subsequently, we coupled molecular docking consensus analysis to screen the best chitinase inhibitor among acridine derivatives. We observed that 3 compounds displayed potential enhanced activity as fungal chitinase inhibitors, showing that compound 5 is the most active molecule, with an IC50 of 0.6 ng/µL. In addition, this compound demonstrated a good interaction with the active site of chitinases from Aspergillus fumigatus and Trichoderma harzianum. Additionally, molecular dynamics and free energy demonstrated complex stability for compound 5. Therefore, this study recommends IVS as a powerful tool for drug development. The potential applications are highlighted as this is the first report of spiro-acridine derivatives acting as chitinase inhibitors that can be potentially used as antifungal and antibacterial candidates.
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Quitinasas , Acridinas , Aspergillus fumigatus , Quitinasas/química , Reposicionamiento de Medicamentos , Simulación del Acoplamiento MolecularRESUMEN
Colorectal cancer (CRC) is the third most common worldwide cancer with high mortality. Factors such as more effective screening programs and improvements in treatment modalities have favored a decrease in the incidence and mortality rate of colorectal cancer in the last three decades. Metastatic CRC is incurable in most cases, and therapy using multiple drugs can increase patients' life expectancy by 2 to 3 years. Chemotherapy is the primary treatment, and fluoropyrimidines correspond to the first treatment line. They can be used in monotherapy or therapeutic schemes of oxaliplatin, FOLFOX (intravenous fluorouracil, leucovorin, and oxaliplatin), and CAPOX (oral capecitabine and oxaliplatin) or regimens based on Irinotecan, such FOLFIRI (fluorouracil, leucovorin, and Irinotecan) and CAPIRI (capecitabine and Irinotecan). Like Camptothecin, irinotecan and other analogs have a mechanism of action based on forming a ternary complex with Topoisomerase I and DNA by reversibly binding, providing DNA damage and consequent cell death. This way, topoisomerases are vital enzymes for DNA maintenance and cell viability. Thus, here we will review the main works demonstrating the correlation between the inhibition of different isoforms of topoisomerases and the in vitro cytotoxic activity in colon cancer. The findings revealed that natural compounds, semi-synthetic and synthetic analogs showed potential cytotoxicity against several colon cancer cell lines in vitro and that this activity was often accompanied by the ability to inhibit type I and II topoisomerases, demonstrating that these enzymes can be promising drug targets for the development of new chemotherapeutics against colon cancer.
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A large family of enzymes with the function of hydrolyzing peptide bonds, called peptidases or cysteine proteases (CPs), are divided into three categories according to the peptide chain involved. CPs catalyze the hydrolysis of amide, ester, thiol ester, and thioester peptide bonds. They can be divided into several groups, such as papain-like (CA), viral chymotrypsin-like CPs (CB), papain-like endopeptidases of RNA viruses (CC), legumain-type caspases (CD), and showing active residues of His, Glu/Asp, Gln, Cys (CE). The catalytic mechanism of CPs is the essential cysteine residue present in the active site. These mechanisms are often studied through computational methods that provide new information about the catalytic mechanism and identify inhibitors. The role of computational methods during drug design and development stages is increasing. Methods in Computer-Aided Drug Design (CADD) accelerate the discovery process, increase the chances of selecting more promising molecules for experimental studies, and can identify critical mechanisms involved in the pathophysiology and molecular pathways of action. Molecular dynamics (MD) simulations are essential in any drug discovery program due to their high capacity for simulating a physiological environment capable of unveiling significant inhibition mechanisms of new compounds against target proteins, especially CPs. Here, a brief approach will be shown on MD simulations and how the studies were applied to identify inhibitors or critical information against cysteine protease from several microorganisms, such as Trypanosoma cruzi (cruzain), Trypanosoma brucei (rhodesain), Plasmodium spp. (falcipain), and SARS-CoV-2 (Mpro). We hope the readers will gain new insights and use our study as a guide for potential compound identifications using MD simulations.
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The N-acylhydrazone function has been reported as a pharmacophore group of molecules with diverse pharmacological activities, including anti-inflammatory effects. Therefore, this study was designed to evaluate the anti-inflammatory potential of the compound N'-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide (JR19) in vivo. The study started with the carrageenan-induced peritonitis model, followed by an investigation of leukocyte migration using the subcutaneous air pouch test and an assessment of the antinociceptive profile using formalin-induced pain. A preliminary molecular docking study focusing on the crystallographic structures of NFκB, iNOS, and sGC was performed to determine the likely mechanism of action. The computational study revealed satisfactory interaction energies with the selected targets, and the same peritonitis model was used to validate the involvement of the nitric oxide pathway and cytokine expression in the peritoneal exudate of mice pretreated with L-NAME or methylene blue. In the peritonitis assay, JR19 (10 and 20 mg/kg) reduced leukocyte migration by 59% and 52%, respectively, compared to the vehicle group, with the 10 mg/kg dose used in subsequent assays. In the subcutaneous air pouch assay, the reduction in cell migration was 66%, and the response to intraplantar formalin was reduced by 39%, particularly during the inflammatory phase, suggesting that the compound lacks central analgesic activity. In addition, a reversal of the anti-inflammatory effect was observed in mice pretreated with L-NAME or methylene blue, indicating the involvement of iNOS and sGC in the anti-inflammatory response of JR19. The compound effectively and significantly decreased the levels of IL-6, TNF-α, IL-17, and IFN-γ, and this effect was reversed in animals pretreated with L-NAME, supporting a NO-dependent anti-inflammatory effect. In contrast, pretreatment with methylene blue only reversed the reduction in TNF-α levels. Therefore, these results demonstrate the pharmacological potential of the novel N-acylhydrazone derivative, which acts through the nitric oxide pathway and cytokine signaling, making it a strong candidate as an anti-inflammatory and immunomodulatory agent.
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The present study proposed the synthesis of a novel acridine derivative not yet described in the literature, chemical characterization by NMR, MS, and IR, followed by investigations of its antileishmanial potential. In vitro assays were performed to assess its antileishmanial activity against L. amazonensis strains and cytotoxicity against macrophages through MTT assay and annexin V-FITC/PI, and the ability to perform an immunomodulatory action using CBA. To investigate possible molecular targets, its interaction with DNA in vitro and in silico targets were evaluated. As results, the compound showed good antileishmanial activity, with IC50 of 6.57 (amastigotes) and 94.97 (promastigotes) µg mL-1, associated with non-cytotoxicity to macrophages (CC50 > 256.00 µg mL-1). When assessed by flow cytometry, 99.8% of macrophages remained viable. The compound induced an antileishmanial effect in infected macrophages and altered TNF-α, IL-10 and IL-6 expression, suggesting a slight immunomodulatory activity. DNA assay showed an interaction with the minor grooves due to the hyperchromic effect of 47.53% and Kb 1.17 × 106 M-1, and was sustained by docking studies. Molecular dynamics simulations and MM-PBSA calculations propose cysteine protease B as a possible target. Therefore, this study demonstrates that the new compound is a promising molecule and contributes as a model for future works.
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Topoisomerase inhibitors are extensively used in cancer chemotherapy. In the process of identifying novel anticancer compounds, biological evaluations are crucial and include, among others, the use of in silico and in vitro approaches. This work aimed to present recent research involving the obtainment and in silico and in vitro evaluation of topoisomerase I, II, and double inhibitors, of synthetic and natural origin, as potential compounds against tumor cells, in addition to proposing the construction of a desirable enzyme catalytic site. Therefore, it was observed that most Topoisomerase I inhibitors presented medium to large structures, with a rigid portion and a flexible region. In contrast, Topoisomerase IIα inhibitors showed medium and large structural characteristics, in addition to the planarity of the aromatic rings, which are mitigated due to flexible rings but may also present elements that restrict conformation. Most compounds that exhibit dual inhibitory activity had relatively long chains, in addition to a flat and rigid portion suggestive of affinity for Topo I and a flexible region characteristic of selective drugs for Topo II. Besides, it is noticed that most compounds that exhibit dual inhibitory showed similarities in the types of interactions and amino acids when compared to the selective compounds of Topo I and II. For instance, selective Topoisomerase I inhibitors interact with Arginine364 residues, and selective Topoisomerase II inhibitors interact with Arginine487 residues, as both residues are targets for dual compounds.
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Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/química , Proliferación Celular , ADN-Topoisomerasas de Tipo II/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Neoplasias/tratamiento farmacológico , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/uso terapéutico , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/metabolismoRESUMEN
The Flaviviridae virus family consists of the genera Hepacivirus, Pestivirus, and Flavivirus, with approximately 70 viral types that use arthropods as vectors. Among these diseases, dengue (DENV) and zika virus (ZIKV) serotypes stand out, responsible for thousands of deaths worldwide. Due to the significant increase in cases, the World Health Organization (WHO) declared DENV a potential threat for 2019 due to being transmitted by infected travelers. Furthermore, ZIKV also has a high rate of transmissibility, highlighted in the outbreak in 2015, generating consequences such as Guillain-Barré syndrome and microcephaly. According to clinical outcomes, those infected with DENV can be asymptomatic, and in other cases, it can be lethal. On the other hand, ZIKV has severe neurological symptoms in newborn babies and adults. More serious symptoms include microcephaly, brain calcifications, intrauterine growth restriction, and fetal death. Despite these worrying data, no drug or vaccine is approved to treat these diseases. In the drug discovery process, one of the targets explored against these diseases is the NS2B-NS3 complex, which presents the catalytic triad His51, Asp75, and Ser135, with the function of cleaving polyproteins, with specificity for basic amino acid residues, Lys- Arg, Arg-Arg, Arg-Lys or Gln-Arg. Since NS3 is highly conserved in all DENV serotypes and plays a vital role in viral replication, this complex is an excellent drug target. In recent years, computer-aided drug discovery (CADD) is increasingly essential in drug discovery campaigns, making the process faster and more cost-effective, mainly explained by discovering new drugs against DENV and ZIKV. Finally, the main advances in computational methods applied to discover new compounds against these diseases will be presented here. In fact, molecular dynamics simulations and virtual screening is the most explored approach, providing several hit and lead compounds that can be used in further optimizations. In addition, fragment-based drug design and quantum chemistry/molecular mechanics (QM/MM) provides new insights for developing anti-DENV/ZIKV drugs. We hope that this review offers further helpful information for researchers worldwide and stimulates the use of computational methods to find a promising drug for treating DENV and ZIKV.
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Dengue , Microcefalia , Infección por el Virus Zika , Virus Zika , Recién Nacido , Humanos , Infección por el Virus Zika/tratamiento farmacológico , Replicación Viral , Dengue/tratamiento farmacológico , Proteínas no Estructurales ViralesRESUMEN
A peptic ulcer is a lesion located in the esophagus, stomach, and upper intestine, caused by an imbalance between acid secretion and the release of protective mucus. This pathology is prevalent in approximately 14% of the world population and is commonly treated with proton pump inhibitors and type 2 histaminergic receptor antagonists, however, these drugs present concerning side effects that may lead to gastric cancer. In this sense, this research aimed to present the main heterocyclics studied in recent years. The screening method for the choice of articles was based on the selection of publications between 2000 and 2021 present in the Science Direct, Web of Science, Capes, and Scielo databases, by using the descriptors ''new derivatives'', "heterocyclics" "antiulcerogenic", "gastroprotective" and "antisecretor". This research showed that the most used rings in the development of anti-ulcer drugs were benzimidazole, quinazoline, thiazole, and thiadiazole. The results also portray several types of modern in silico, in vitro and in vivo assays, as well as the investigation of different mechanisms of action, with emphasis on proton pump inhibition, type 2 histaminergic receptor blockers, potassium competitive acid blockers, type E prostaglandin agonism, anti-secretory activity and anti-oxidant action. Additionally, the review evidenced the presence of the nitrogen atom in the heterocyclic ring as a determinant of the potential of the compound. This research suggests new alternatives for the treatment of gastric lesions, which may be more potent and cause fewer side effects than the currently used, and tend to evolve into more advanced studies in the coming years.
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Antiulcerosos , Úlcera Péptica , Antiulcerosos/farmacología , Antiulcerosos/uso terapéutico , Antagonistas de los Receptores H2 de la Histamina/farmacología , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Humanos , Úlcera Péptica/tratamiento farmacológico , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/uso terapéuticoRESUMEN
The compound (E)-2-cyano-N,3-diphenylacrylamide (JMPR-01) was structurally developed using bioisosteric modifications of a hybrid prototype as formed from fragments of indomethacin and paracetamol. Initially, in vitro assays were performed to determine cell viability (in macrophage cultures), and its ability to modulate the synthesis of nitrite and cytokines (IL-1ß and TNFα) in non-cytotoxic concentrations. In vivo, anti-inflammatory activity was explored using the CFA-induced paw edema and zymosan-induced peritonitis models. To investigate possible molecular targets, molecular docking was performed with the following crystallographic structures: LT-A4-H, PDE4B, COX-2, 5-LOX, and iNOS. As results, we observed a significant reduction in the production of nitrite and IL-1ß at all concentrations used, and also for TNFα with JMPR-01 at 50 and 25 µM. The anti-edematogenic activity of JMPR-01 (100 mg/kg) was significant, reducing edema at 2-6 h, similar to the dexamethasone control. In induced peritonitis, JMPR-01 reduced leukocyte migration by 61.8, 68.5, and 90.5% at respective doses of 5, 10, and 50 mg/kg. In silico, JMPR-01 presented satisfactory coupling; mainly with LT-A4-H, PDE4B, and iNOS. These preliminary results demonstrate the strong potential of JMPR-01 to become a drug for the treatment of inflammatory diseases.
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BACKGROUND: Acridine compounds have been described as promising anticancer agents. Previous studies showed that (E)-1'-((4-chlorobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-06), a spiro-acridine compound, has antitumor activity on Ehrlich tumor and low toxicity. Herein, we investigated its antitumor effect against human cells in vitro. METHODS: MTT assay was used to assess cytotoxicity of AMTAC-06 (3.125-200 µM) against tumor and non-tumor cells, and the half-maximal inhibitory concentration (IC50) and the selectivity index (SI) were calculated. The effects on the cell cycle (propidium iodide-PI-staining), apoptosis (Annexin V-FITC/PI double staining by flow cytometry), and production of reactive oxygen species, ROS (DCFH assay) were also evaluated. Statistical analysis was achieved using ANOVA followed by Tukey's post-test. RESULTS: AMTAC-06 showed higher cytotoxicity against colorectal carcinoma HCT-116 cells (IC50: 12.62 µM). The SI showed that AMTAC-06 was more selective for HCT-116 cells (HaCaT SI: 1.41; PBMC SI: 0.62) than doxorubicin (HaCaT SI: 0.10; PBMC SI: 0.01). AMTAC-06 (15 and 30 µM) induced an increase in the sub-G1 peak (p < 0.000001) and cell cycle arrest in S phase (p = 0.003547). Moreover, treatment with this compound (15 and 30 µM) resulted in increased early (p < 0.000001) and late apoptotic cells (p < 0.000001). In addition, there was a reduction on ROS production (p < 0.000001). CONCLUSIONS: AMTAC-06 presents anticancer activity against HCT-116 cells by regulating the cell cycle, inducing apoptosis and an antioxidant action.
Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Compuestos de Espiro , Acridinas/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/tratamiento farmacológico , Células HCT116 , Humanos , Leucocitos Mononucleares/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Espiro/farmacologíaRESUMEN
In this study, we report the synthesis of eight novel indole-thiazole and indole-thiazolidinone derivatives, as well as their ability to interact with DNA, analysed through the UV-vis absorption, fluorescence, circular dichroism (CD), viscosity techniques and molecular docking. The ctDNA interaction analysis demonstrated different spectroscopic effects and the affinity constants (Kb) calculated by the UV-vis absorption method were between 2.08 × 105 and 6.99 × 106 M-1, whereas in the fluorescence suppression constants (Ksv) ranged between 0.38 and 0.77 × 104 M-1 and 0.60-7.59 × 104 M-1 using Ethidium Bromide (EB) and 4',6-Diamidino-2-phenylindole (DAPI) as fluorescent probes, respectively. Most derivatives did not alter significantly the secondary structure of the ctDNA according to the CD results. None of the compounds was able to change the relative viscosity of the ctDNA. These results prove that compounds interact with ctDNA via groove binding, which was confirmed by A-T rich oligonucleotide sequence assay with compound JF-252, suggesting the importance of both the phenyl ring coupled to C-4 thiazole ring and the bromo-unsubstituted indole nucleus.
Asunto(s)
ADN/química , Indoles/química , Tiazoles/química , Dicroismo Circular/métodos , Etidio/química , Colorantes Fluorescentes/química , Simulación del Acoplamiento Molecular/métodos , Espectrometría de Fluorescencia/métodos , TermodinámicaRESUMEN
Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes.