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Polyenes are a class of organic compounds well known for their potent antifungal properties. They are effective due to their ability to target and disrupt fungal cell membranes by binding to ergosterol and forming pores. Despite their effectiveness as antifungal drugs, polyenes have several limitations, such as high toxicity to the host cell and poor solubility in water. This has prompted ongoing research to develop safer and more efficient derivatives to overcome such limitations while enhancing their antifungal activity. In this review article, we present a thorough analysis of polyene derivatives, their structural modifications, and their influence on their therapeutic effects against various fungal strains. Key studies are discussed, illustrating how structural modifications have led to improved antifungal properties. By evaluating the latest advancements in the synthesis of polyene derivatives, we highlight that incorporating amide linkers at the carboxylic moiety of polyene molecules notably improves their antifungal properties, as evidenced by derivatives 4, 5, 6G, and 18. This review can help in the design and development of novel polyene-based compounds with potent antifungal activities.
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A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Piperazinas , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Piperazinas/farmacología , Piperazinas/química , Piperazinas/síntesis química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Anhidrasas Carbónicas/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/química , Piperazina/química , Piperazina/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Células HT29 , Relación Estructura-Actividad , Línea Celular Tumoral , Estructura Molecular , Células A549RESUMEN
Cancer is ranked among lethal diseases globally, and the increasing number of cancer cases and deaths results from limited access to effective therapeutics. The use of plant-based medicine has been gaining interest from several researchers. Carvacrol and its isomeric compound, thymol, are plant-based extracts that possess several biological activities, such as antimalarial, anticancer, antifungal, and antibacterial. However, their efficacy is compromised by their poor bioavailability. Thus, medicinal scientists have explored the synthesis of hybrid compounds containing their pharmacophores to enhance their therapeutic efficacy and improve their bioavailability. Hence, this review is a comprehensive report on hybrid compounds containing carvacrol and its isomer, thymol, with potent anticancer and antibacterial agents reported between 2020 and 2024. Furthermore, their structural activity relationship (SAR) and recommended future strategies to further enhance their therapeutic effects will be discussed.
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Antibacterianos , Antineoplásicos , Cimenos , Timol , Timol/química , Timol/farmacología , Cimenos/química , Cimenos/farmacología , Cimenos/uso terapéutico , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Relación Estructura-Actividad , Neoplasias/tratamiento farmacológico , AnimalesRESUMEN
Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the ß-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea. Evaluation of their antiproliferative activities in vitro revealed that N-9 substituted triazole-type harmiprime was the most selective compound against MCF-7, whereas C1-substituted ureido-type hybrid was the most active compound against all cell lines tested. On the other hand, dimeric harmiprime was not toxic at all. Although spectrophotometric studies and thermal denaturation experiments indicated binding of harmiprims to the ds-DNA groove, cell localization showed that harmiprims do not enter cell nucleus nor mitochondria, thus no inhibition of DNA-related processes can be expected. Cell cycle analysis revealed that C1-substituted ureido-type hybrid induced a G1 arrest and reduced the number of cells in the S phase after 24 h, persisting at 48 h, albeit with a less significant increase in G1, possibly due to adaptive cellular responses. In contrast, N-9 substituted triazole-type harmiprime exhibited less pronounced effects on the cell cycle, particularly after 48 h, which is consistent with its moderate activity against the MCF-7 cell line. On the other hand, screening of their antiplasmodial activities against the erythrocytic, hepatic, and gametocytic stages of the Plasmodium life cycle showed that dimeric harmiprime exerts powerful triple-stage antiplasmodial activity, while computational analysis showed its binding within the ATP binding site of PfHsp90.
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Antimaláricos , Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Harmina , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Harmina/farmacología , Harmina/química , Harmina/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Plasmodium falciparum/efectos de los fármacos , Estructura Molecular , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Pruebas de Sensibilidad ParasitariaRESUMEN
Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from MI metal ions with thioureas, aiming to obtain potential leishmanicidal agents. The thiourea ligands (HLR) were obtained by reactions of p-toluenesulfohydrazide with R-isothiocyanates and were used in complexation reactions with AgI and AuI, leading to the formation of complexes of composition [M(HLR)2]X (M = Ag or Au; X = NO3- or Cl-). All compounds were characterized by FTIR, 1H NMR, UV-vis, emission spectroscopy and elemental analysis. Some representatives were additionally studied by ESI-MS and single-crystal XRD. Their properties were further analyzed by DFT calculations. Their cytotoxicity on Vero cells and the extracellular leishmanicidal activity on Leishmania infantum and Leishmania braziliensis cells were evaluated. Additionally, the interaction of the complexes with the Old Yellow enzyme of the L. braziliensis (LbOYE) was examined. The biological tests showed that some compounds present remarkable leishmanicidal activity, even higher than that of the standard drug Glucantime, with different selectivity for the two species of Leishmania. Finally, the interaction studies with LbOYE revealed that this enzyme could be one of their biological targets.
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Two novel hybrid compounds, CON1 and CON2, have been developed by combining sclareol (SC) and doxorubicin (DOX) into a single molecular entity. These hybrid compounds have a 1:1 molar ratio of covalently linked SC and DOX. They have demonstrated promising anticancer properties, especially in glioblastoma cells, and have also shown potential in treating multidrug-resistant (MDR) cancer cells that express the P-glycoprotein (P-gp) membrane transporter. CON1 and CON2 form nanoparticles, as confirmed by Zetasizer, transmission electron microscopy (TEM), and chemical modeling. TEM also showed that CON1 and CON2 can be found in glioblastoma cells, specifically in the cytoplasm, different organelles, nucleus, and nucleolus. To examine the anticancer properties, the U87 glioblastoma cell line, and its corresponding multidrug-resistant U87-TxR cell line, as well as patient-derived astrocytoma grade 3 cells (ASC), were used, while normal human lung fibroblasts were used to determine the selectivity. CON1 and CON2 exhibited better resistance and selectivity profiles than DOX, showing less cytotoxicity, as evidenced by real-time cell analysis, DNA damage determination, cell death induction, mitochondrial respiration, and mitochondrial membrane depolarization studies. Cell cycle analysis and the ß-galactosidase activity assay suggested that glioblastoma cells die by senescence following CON1 treatment. Overall, CON1 and CON2 showed great potential as they have better anticancer features than DOX. They are promising candidates for additional preclinical and clinical studies on glioblastoma.
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Doxorrubicina , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Doxorrubicina/farmacología , Línea Celular Tumoral , Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Diterpenos/farmacología , Diterpenos/química , Nanopartículas/química , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Daño del ADN/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacosRESUMEN
Ursodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides their well-known primary biological roles, both compounds possess the ability to influence a variety of cellular processes involved in the etiology of various diseases. These reasons suggested the potential of acetoacetate-UDCA hybrids as possible therapeutic agents and prompted us to develop a synthetic strategy to selectively derivatize the hydroxyl groups of the bile acid with acetoacetyl moieties. 3α-acetoacetoxy UDCA was obtained (60% isolated yield) via the regioselective transesterification of methyl acetoacetate with UDCA promoted by the Candida antarctica lipase B (CAL-B). 3α,7ß-bis-acetoacetoxy UDCA was obtained instead by thermal condensation of methyl acetoacetate and UDCA (80% isolated yield). This bis-adduct was finally converted to the 7ß-acetoacetoxy UDCA (82% isolated yield) via CAL-B catalyzed regioselective alcoholysis of the ester group on the 3α position. In order to demonstrate the value of the above new hybrids as UDCA-based scaffolds, 3α-acetoacetoxy UDCA was subjected to multicomponent Biginelli reaction with benzaldehyde and urea to obtain the corresponding 4-phenyl-3,4-dihydropyrimidin-2-(1H)-one derivative in 65% isolated yield.
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Acetoacetatos , Ácido Ursodesoxicólico , Humanos , Ácidos y Sales BiliaresRESUMEN
Considering the pivotal role of angiogenesis in solid tumor progression, we developed a novel series of quinazoline-thiazole hybrids (SA01-SA07) as antiproliferative and anti-angiogenic agents. Four out of the seven compounds displayed superior antiproliferative activity (IC50 =1.83-4.24 µM) on HepG2 cells compared to sorafenib (IC50 = 6.28 µM). The affinity towards the VEGFR2 kinase domain was assessed through in silico prediction by molecular docking, molecular dynamics studies, and MM-PBSA. The series displayed a high degree of similarity to sorafenib regarding the binding pose within the active site of VEGFR2, with a different orientation of the 4-substituted-thiazole moieties in the allosteric pocket. Molecular dynamics and MM-PBSA evaluations identified SA05 as the hybrid forming the most stable complex with VEGFR2 compared to sorafenib. The impact of the compounds on vascular cell proliferation was assessed on EA.hy926 cells. Six compounds (SA01-SA05, SA07) displayed superior anti-proliferative activity (IC50 = 0.79-5.85 µM) compared to sorafenib (IC50 = 6.62 µM). The toxicity was evaluated on BJ cells. Further studies of the anti-angiogenic effect of the most promising compounds, SA04 and SA05, through the assessment of impact on EA.hy296 motility using a wound healing assay and in ovo potential in a CAM assay compared to sorafenib, led to the confirmation of the anti-angiogenic potential.
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Antineoplásicos , Sorafenib/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Simulación del Acoplamiento Molecular , Quinazolinas/farmacología , Quinazolinas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de la Angiogénesis/farmacología , Proliferación Celular , Estructura MolecularRESUMEN
A series of novel triazole-tethered ferrocenoylamino-substituted cinchona-chalcone hybrids along with two representative benzoylamino-substituted reference compounds were prepared by three methods of CuAAC chemistry. In line with the limited success or complete failure of attempted conversions with low catalyst loadings, by means of DFT modeling studies, we demonstrated that a substantial part of the Cu(I) ions can be chelated and thus trapped in the aroylamino-substituted cinchona fragment and all of the accessible coordinating sites of the chalcone residues. Accordingly, increased amounts of catalysts were used to achieve acceptable yields; however, the cycloadditions with para-azidochalcones were accompanied by partial or complete aldehyde-forming hydrolytic fission of the enone C=C bond in a substituent-, solvent- and copper load-dependent manner. The experienced hydrolytic stability of the hybrids obtained by cycloadditions with ortho-azidochalcones was interpreted in terms of relative energetics, DFT reactivity indices and MO analysis of simplified models of two isomer copper-enone complexes. The novel hybrids were evaluated on HeLa, MDA-MB-231 and A2780 cell lines and showed substantial activity at low-to-submicromolar concentrations. An organometallic model carrying 3,4,5-trimethoxyphenyl residue in the enone part with a para-disubstituted benzene ring in the central skeletal region was identified as the most potent antiproliferative lead, characterized by submicromolar IC50 values measured on the three investigated cells. The biological assays also disclosed that this ferrocenoylamino-containing lead compound displays a ca. two- to five-fold more substantial antiproliferative effect than its benzoylamino-substituted counterpart.
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Antimicrobial resistance is an increasing problem for global public health. One of the strategies to combat this issue is the synthesis of novel antimicrobials through rational drug design based on extensive structure-activity relationship studies. The thiazole nucleus is a prominent feature in the structure of many authorized antimicrobials, being clubbed with different heterocycles. The purpose of this review is to study the structure-activity relationship in antimicrobial thiazoles clubbed with various heterocycles, as reported in the literature between 2017 and 2023, in order to offer an overview of the last years in terms of antimicrobial research and provide a helpful instrument for future research in the field.
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Natural products are a very rich source for obtaining new compounds with therapeutic potential. In the search for new antiparasitic and antimicrobial agents, molecular hybrids were designed based on the structures of antimicrobial marine quinazolinones and eugenol, a natural phenolic compound. Following reports of the therapeutic potential of quinazolinones and eugenol derivatives, it was expected that the union of these pharmacophores could generate biologically relevant substances. The designed compounds were obtained by classical synthetic procedures and were characterized by routine spectrometric techniques. Nine intermediates and final products were then evaluated in vitro against Trypanosoma brucei and Leishmania infantum. Antifungal and antibacterial activity were also evaluated. Six compounds (9b, 9c, 9d, 10b, 10c, and 14) showed mild activity against T. brucei with IC50 in the range of 11.17-31.68 µM. Additionally, intermediate 9c showed anti-Leishmania activity (IC50 7.54 µM) and was six times less cytotoxic against THP-1 cells. In conclusion, novel derivatives with a simple quinazolinone scaffold showing selectivity against parasites without antibacterial and antifungal activities were disclosed, paving the way for new antitrypanosomal agents.
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Antiinfecciosos , Antiprotozoarios , Leishmania infantum , Trypanosoma brucei brucei , Antifúngicos/farmacología , Eugenol , Antiprotozoarios/química , Antibacterianos/farmacología , Quinazolinonas/química , Relación Estructura-ActividadRESUMEN
The anticarcinogenic potential of a series of 1,5-disubstituted tetrazole-1,2,3-triazole hybrids (T-THs) was evaluated in the breast cancer (BC)-derived cell lines MCF-7 (ER+, PR+, and HER2-), CAMA-1 (ER+, PR+/-, and HER2-), SKBR-3 (ER+, PR+, and HER2+), and HCC1954 (ER+, PR+, and HER2+). The T-THs 7f, 7l, and 7g inhibited the proliferation of MCF-7 and CAMA-1, HCC1954, and SKBR-3 cells, respectively. The compounds with stronger effect in terms of migration and invasion inhibition were 7o, 7b, 7n, and 7k for the CAMA-1, MCF-7, HCC1954, and SKBR-3 cells respectively. Interestingly, these T-THs were the compounds with a fluorine present in their structures. To discover a possible target protein, a molecular docking analysis was performed for p53, p38, p58, and JNK1. The T-THs presented a higher affinity for p53, followed by JNK1, p58, and lastly p38. The best-predicted affinity for p53 showed interactions between the T-THs and both the DNA fragment and the protein. These results provide an opportunity for these compounds to be studied as potential drug candidates for breast cancer treatment.
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Neoplasias de la Mama , Humanos , Femenino , Células MCF-7 , Neoplasias de la Mama/metabolismo , Proteína p53 Supresora de Tumor , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Triazoles/química , Proliferación CelularRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative pathology among progressive dementias, and it is characterized by the accumulation in the brain of extracellular aggregates of beta-amyloid proteins and neurofibrillary intracellular tangles consisting of τ-hyperphosphorylated proteins. Under normal conditions, beta-amyloid peptides exert important trophic and antioxidant roles, while their massive presence leads to a cascade of events culminating in the onset of AD. The fibrils of beta-amyloid proteins are formed by the process of fibrillogenesis that, starting from individual monomers of beta-amyloid, can generate polymers of this protein, constituting the hypothesis of the "amyloid cascade". To date, due to the lack of pharmacological treatment for AD without toxic side effects, chemical research is directed towards the realization of hybrid compounds that can act as an adjuvant in the treatment of this neurodegenerative pathology. The hybrid compounds used in this work include moieties of a hydroxytyrosol, a nitrohydroxytyrosol, a tyrosol, and a homovanillyl alcohol bound to the N-benzylpiperidine moiety of donepezil, the main drug used in AD. Previous experiments have shown different properties of these hybrids, including low toxicity and antioxidant and chelating activities. The purpose of this work was to test the effects of hybrid compounds mixed with Aß1-40 to induce fibrillogenesis and mimic AD pathogenesis. This condition has been studied both in test tubes and by an in vitro model of neuronal differentiated human SH-SY5Y neuroblastoma cells. The results obtained from test tube experiments showed that some hybrids inhibit the activity of the enzymes AChE, BuChE, and BACE-1. Cell experiments suggested that hybrids could inhibit fibrillogenesis, negatively modulating caspase-3. They were also shown to exert antioxidant effects, and the acetylated hybrids were found to be more functional and efficient than nonacetylated forms.
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Enfermedad de Alzheimer , Neuroblastoma , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Donepezilo/farmacología , Antioxidantes/farmacología , Neuroblastoma/tratamiento farmacológico , Proteínas tauRESUMEN
Natural products (NPs) are highly profitable pharmacological tools due to their chemical diversity and ability to modulate biological systems. Accessing new chemical entities while retaining the biological relevance of natural chemotypes is a fundamental goal in the design of novel bioactive compounds. Notably, NPs have played a crucial role in understanding Hedgehog (HH) signalling and its pharmacological modulation in anticancer therapy. However, HH antagonists developed so far have shown several limitations, thus growing interest in the design of second-generation HH inhibitors. Through smart manipulation of the NPs core-scaffold, unprecedented and intriguing architectures have been achieved following different design strategies. This study reports the rational design and synthesis of a first and second generation of anthraquinone-based hybrids by combining the rhein scaffold with variously substituted piperazine nuclei that are structurally similar to the active portion of known SMO antagonists, the main transducer of the HH pathway. A thorough functional and biological investigation identified RH2_2 and RH2_6 rhein-based hybrids as valuable candidates for HH inhibition through SMO antagonism, with the consequent suppression of HH-dependent tumour growth. These findings also corroborated the successful application of the NPs-based hybrid design strategy in the development of novel NP-based SMO antagonists.
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Antineoplásicos , Neoplasias , Humanos , Receptor Smoothened/uso terapéutico , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antraquinonas/farmacología , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Coumarin-pyrimidine hybrid compounds were synthesized by condensation reaction of α,ß-unsaturated ketones of 6-acetyl-5-hydroxy-4-methylcoumarin with guanidine. The reaction yields were of 42-62%. The antidiabetic and anticancer activities of these compounds were examined. These compounds displayed low toxicity to two cancer cell lines (including KB and HepG2 ones), but exhibited remarkably active against α-amylase with IC50 values of 102.32 ± 1.15 µM to 249.52 ± 1.14 µM and against α-glucosidase with IC50 values of 52.16 ± 1.12 µM to 184.52 ± 1.15 µM. Amongst these compounds, 6c was the best inhibitory activity against α-amylase, and 6f had the highest activity against α-glucosidase. The kinetics of inhibitor 6f was competitive α-glucosidase inhibitor property. ADMET predictions showed that almost all synthesized compounds exhibited drug-like activity. IFD and MD simulations were carried out on enzymes 4W93 and 5NN8 to elucidate inhibitory potential of 6c and 6f against tested enzymes. The binding free energy calculation by MM-GBSA approach showed that Coulomb, lipophilic and van der Waals energy terms are major contributors for the inhibitor binding. Molecular dynamics simulations in water solvent system were carried out for the 6f/5NN8 complex to elucidate the variability of active interactions between ligand 6f and active pockets of this enzyme.
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Curcumin and oleanolic acid are natural compounds with high potential in medicinal chemistry. These products have been widely studied for their pharmacological properties and have been structurally modified to improve their bioavailability and therapeutic value. In the present study, we discuss how these compounds are utilized to develop bioactive hybrid compounds that are intended to target cancer cells. Using a bifunctional linker, succinic acid, to combine curcumin and triterpenoic oleanolic acid, several hybrid compounds were prepared. Their cytotoxicity against different cancer cell lines was evaluated and compared with the activity of curcumin (the IC50 value (24 h), for MCF7, HeLaWT and HT-29 cancer cells for KS5, KS6 and KS8 compounds was in the range of 20.6-94.4 µM, in comparison to curcumin 15.6-57.2 µM). Additionally, in silico studies were also performed. The computations determined the activity of the tested compounds towards proteins selected due to their similar binding modes and the nature of hydrogen bonds formed within the cavity of ligand-protein complexes. Overall, the curcumin-triterpene hybrids represent an important class of compounds for the development of effective anticancer agents also without the diketone moiety in the curcumin molecule. Moreover, some structural modifications in keto-enol moiety have led to obtaining more information about different chemical and biological activities. Results obtained may be of interest for further research into combinations of curcumin and oleanolic acid derivatives.
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BACKGROUND: Statins present a plethora of pleiotropic effects including anti-inflammatory and antimicrobial responses. A,α-difluorophenylacetamides, analogs of diclofenac, are potent pre-clinical anti-inflammatory non-steroidal drugs. Molecular hybridization based on the combination of pharmacophoric moieties has emerged as a strategy for the development of new candidates aiming to obtain multitarget ligands. METHODS: Considering the anti-inflammatory activity of phenylacetamides and the potential microbicidal action of statins against obligate intracellular parasites, the objective of this work was to synthesize eight new hybrid compounds of α,α-difluorophenylacetamides with the moiety of statins and assess their phenotypic activity against in vitro models of Plasmodium falciparum and Trypanosoma cruzi infection besides exploring their genotoxicity safety profile. RESULTS: None of the sodium salt compounds presented antiparasitic activity and two acetated compounds displayed mild anti-P. falciparum effect. Against T. cruzi, the acetate halogenated hybrids showed moderate effect against both parasite forms relevant for human infection. Despite the considerable trypanosomicidal activity, the brominated compound revealed a genotoxic profile impairing future in vivo testing. CONCLUSIONS: However, the chlorinated derivative was the most promising compound with chemical and biological profitable characteristics, without presenting genotoxicity in vitro, being eligible for further in vivo experiments.
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Despite enormous advances in terms of therapeutic strategies, multiple myeloma (MM) still remains an incurable disease with MM patients often becoming resistant to standard treatments. To date, multiple combined and targeted therapies have proven to be more beneficial compared to monotherapy approaches, leading to a decrease in drug resistance and an improvement in median overall survival in patients. Moreover, recent breakthroughs highlighted the relevant role of histone deacetylases (HDACs) in cancer treatment, including MM. Thus, the simultaneous use of HDAC inhibitors with other conventional regimens, such as proteasome inhibitors, is of interest in the field. In this review, we provide a general overview of HDAC-based combination treatments in MM, through a critical presentation of publications from the past few decades related to in vitro and in vivo studies, as well as clinical trials. Furthermore, we discuss the recent introduction of dual-inhibitor entities that could have the same beneficial effects as drug combinations with the advantage of having two or more pharmacophores in one molecular structure. These findings could represent a starting-point for both reducing therapeutic doses and lowering the risk of developing drug resistance.
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A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 µM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite's plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.
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Antiprotozoarios , Enfermedad de Chagas , Trypanosoma cruzi , Humanos , Antiparasitarios/farmacología , Antiprotozoarios/farmacología , Éteres Fosfolípidos/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Colina/uso terapéuticoRESUMEN
In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 µM) and IC50 > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders.