Hybrid Compounds as Direct Multitarget Ligands: A Review de Oliveira Pedrosa, Michelle; Duarte da Cruz, Rayssa Marques; de Oliveira Viana, Jessika ...
Current topics in medicinal chemistry,
04/2017, Volume:
17, Issue:
9
Journal Article
Peer reviewed
Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single ...molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost. The approach has been successfully used by many research groups around the world and has had very promising results with diseases having multifactorial profiles, like Alzheimer´s, Parkinson´s disease, cancer, inflammation, and hypertension among others. The purpose of this paper is to conduct an updated review of molecular hybridization and multitarget profiling (a rational drug design approach), and its applications to the design and discovery of novel hybrid compounds with anti-inflammatory, antimicrobial, anticancer and antiprotozoal (leishmaniasis, malaria, and schistosomiasis) activities over the last six years.
Protozoal diseases, such as leishmaniasis, malaria, African sleeping sickness, Chagas disease, amoebiasis, giardiasis, cryptococcosis, and toxoplasmosis (among others), affect and/or have the ...potential to infect more than one billion people worldwide ....
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The ever increasing number of multidrug-resistant microorganism pathogens has become a great and global public health threat. Antibiotic mechanisms of action and the opposing mechanisms of resistance ...are intimately associated, but comprehension of the biochemical and molecular functions of such drugs is not a simple exercise. Both the environment, and genetic settings contribute to alterations in phenotypic resistance (natural bacterial evolution), and make it difficult to control the emergence and impacts of antibiotic resistance. Under such circumstances, comprehension of how bacteria develop and/or acquire antibiotic resistance genes (ARG) has a critical role in developing propositions to fight against these superbugs, and to search for new drugs. In this review, we present and discuss both general information and examples of common genetic and molecular mechanisms related to antibiotic resistance, as well as how the expression and interactions of ARGs are important to drug resistance. At the same time, we focus on the recent achievements in the search for antibiotic adjuvants, which help combat antibiotic resistance through deactivation of bacterial mechanisms of action such as β-lactamases. Recent advances involving the use of anti-resistance drugs such as: efflux pump inhibitors; anti-virulence drugs; drugs against quorum sensing; and against type II/III secretion systems are revealed. Such antibiotic adjuvants (as explored herein) collaborate against the problems of antibiotic resistance, and may restore or prolong the therapeutic activity of known antibiotics.
Flavonoids are phenolic compounds, secondary metabolites of plants that cause several benefits to our health, including helping the treatment against cancer. These pharmacological properties are ...associated with the ability of flavonoids in attenuating the generation of reactive oxygen species, acting as chelate compounds or affecting the oxi-redox cycle. In spite of the large number of information in term of SAR and QSAR, no recent review has tabulated and discussed in detail these data. In view of this, we bring here a detailed discussion of the structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) models. We have also analyzed the correlation between the chemical structure of flavonoids and analogues to their anticancer activities. A large number of methodologies have been used to identify the characteristics of these compounds with their potential anticancer: multiple linear regression, principal components analysis, comparative molecular field analysis, comparative molecular similarity indices analysis, partial least squares, neural networks, configuration of classification and regression trees, Free-Wilson, docking; using topological, structural and enthalpies' descriptors. We also discussed the use of docking models, together with QSAR models, for the virtual screening of anticancer flavonoids. The importance of docking models to the medicinal chemistry of anticancer flavonoids has increased in the last decade, especially to help in identifying the structural determinants responsible for the activity. We tabulated here the most important examples of virtual screening determined for anticancer flavonoids and we highlighted the structural determinants. The mode of action, the most potent anticancer flavonoids and hints for the structural design of anticancer flavonoids are revised in details and provided here.
The term neglected diseases refers to a group of infections caused by various classes of pathogens, including protozoa, viruses, bacteria, and helminths, most often affecting impoverished populations ...without adequate sanitation living in close contact with infectious vectors and domestic animals. The fact that these diseases were historically not considered priorities for pharmaceutical companies made the available treatments options obsolete, precarious, outdated, and in some cases nonexistent. The use of plants for medicinal, religious, and cosmetic purposes has a history dating back to the emergence of humanity. One of the principal fractions of chemical substances found in plants are essential oils (EOs). EOs consist of a mixture of volatile and hydrophobic secondary metabolites with marked odors, composed primarily of terpenes and phenylpropanoids. They have great commercial value and were widely used in traditional medicine, by phytotherapy practitioners, and in public health services for the treatment of several conditions, including neglected diseases. In addition to the recognized cytoprotective and antioxidative activities of many of these compounds, larvicidal, insecticidal, and antiparasitic activities have been associated with the induction of oxidative stress in parasites, increasing levels of nitric oxide in the infected host, reducing parasite resistance to reactive oxygen species, and increasing lipid peroxidation, ultimately leading to serious damage to cell membranes. The hydrophobicity of these compounds also allows them to cross the membranes of parasites as well as the blood-brain barrier, collaborating in combat at the second stage of several of these infections. Based on these considerations, the aim of this review was to present an update of the potential of EOs, their fractions, and their chemical constituents, against some neglected diseases, including American and African trypanosomiasis, leishmaniasis, and arboviruses, specially dengue.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cancer is one of the most urgent problems in medicine. In recent years, cancer is the second leading cause of death globally. In search for more effective and less toxic treatment against cancer, ...natural products are used as prototypes in the synthesis of new anticancer drugs. The aim of this study was to investigate the in vivo toxicity and the mechanism of antitumor action of 7-isopentenyloxycoumarin (UMB-07), a coumarin derivative with antitumor activity. The toxicity was evaluated in vitro (hemolysis assay), and in vivo (micronucleus and acute toxicity assays). Ehrlich ascites carcinoma model was used to evaluate in vivo antitumor activity of UMB-07 (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.), after 9 days of treatment, as well as toxicity. UMB-07 (2000 μg/mL) induced only 0.8% of hemolysis in peripheral blood erythrocytes of mice. On acute toxicity assay, LD
50
(50% lethal dose) was estimated at around 1000 mg/kg (i.p.), and no micronucleated erythrocytes were recorded after UMB-07 (300 mg/kg, i.p.) treatment. UMB-07 (25 and 50 mg/kg) reduced tumor volume and total viable cancer cells. In the mechanism action investigation, no changes were observed on the cell cycle analysis; however, UMB-07 reduced peritumoral microvessels density and CCL2 chemokine levels. In addition, UMB-07 showed weak toxicity on biochemical, hematological, and histological parameters after 9 days of antitumor treatment. The current findings suggest that UMB-07 has low toxicity and exerts antitumor effect by inhibit angiogenesis via CCL2 chemokine decrease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancer is a multifactorial disease that continues to increase. Lignans are known to be important anticancer agents. However, due to the structural diversity of lignans, it is difficult to associate ...anticancer activity with a particular subclass. Therefore, the present study sought to evaluate the association of lignan subclasses with antitumor activity, considering the genetic profile of the variants of the selected targets. To do so, predictive models were built against the targets tyrosine-protein kinase ABL (ABL), epidermal growth factor receptor erbB1 (EGFR), histone deacetylase (HDAC), serine/threonine-protein kinase mTOR (mTOR) and poly ADP-ribose polymerase-1 (PARP1). Then, single nucleotide polymorphisms were mapped, target mutations were designed, and molecular docking was performed with the lignans with the best predicted biological activity. The results showed more anticancer activity in the dibenzocyclooctadiene, furofuran and aryltetralin subclasses. The lignans with the best predictive values of biological activity showed varying binding energy results in the presence of certain genetic variants.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Cervical cancer stands as a prevalent gynaecologic malignancy affecting women globally, often linked to persistent human papillomavirus infection. Biomarkers associated with cervical cancer, ...including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E, show upregulation and are linked to angiogenesis and lymphangiogenesis. This research aims to employ in-silico methods to target tyrosine kinase receptor proteins—VEGFR-1, VEGFR-2, and VEGFR-3, and identify novel inhibitors for Vascular Endothelial Growth Factors receptors (VEGFRs). A comprehensive literary study was conducted which identified 26 established inhibitors for VEGFR-1, VEGFR-2, and VEGFR-3 receptor proteins. Compounds with high-affinity scores, including PubChem ID—25102847, 369976, and 208908 were chosen from pre-existing compounds for creating Deep Learning-based models. RD-Kit, a Deep learning algorithm, was used to generate 43 million compounds for VEGFR-1, VEGFR-2, and VEGFR-3 targets. Molecular docking studies were conducted on the top 10 molecules for each target to validate the receptor-ligand binding affinity. The results of Molecular Docking indicated that PubChem IDs—71465,645 and 11152946 exhibited strong affinity, designating them as the most efficient molecules. To further investigate their potential, a Molecular Dynamics Simulation was performed to assess conformational stability, and a pharmacophore analysis was also conducted for indoctrinating interactions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The protozoa, Trypanosoma cruzi (etiological agent of Chagas diseases – also named American trypanosomiasis) and T. brucei (causative agent of human African trypanosomiasis – HAT), negatively impact ...public health, being endemic in several countries and leading to thousands of deaths per year. Moreover, the pharmacological treatment of diseases has several limitations, such as parasitic resistance and several side effects in patients, which decrease therapeutic adherence. Two cysteine proteases, cruzain (CRZ) from T. cruzi and a cathepsin L-like enzyme ( Tbr CATL) from T. brucei , are considered promising targets of these protozoa since they are responsible for many key biological processes in their life cycles. Coumarin analogs have been reported in diverse studies targeting the development of trypanocidal agents, and have shown activity against different evolutionary forms of these parasites. In this study, we report a virtual fragment-based drug design (vFBDD) approach to develop coumarin-based analogs capable of inhibiting these main cysteine proteases. Also, their experimental validation involved enzymatic inhibition, in vitro infected-cell-based, and antitrypomastigote assays. One compound, FN-27, a coumarin-thiosemicarbazone analog, inhibited both CRZ (IC 50 : 14.4 μM ± 0.02) and Tbr CATL (IC 50 : 2.0 μM ± 0.6), and exhibited trypanocidal activity against T. cruzi amastigote-infected cells (EC 50 : 5.5 μM), but had no effect on T. brucei trypomastigotes. These results suggest that FN-27 probably exerts its mechanism of action against the T. cruzi parasite via inhibition of CRZ, although other targets could be involved. In parallel, FN-10, a coumarin-chalcone analog, was active against T. brucei trypomastigotes (EC 50 : 4.8 μM ± 0.15) but it did not inhibit CRZ or Tbr CATL. Accordingly, FN-10 may exhibit its effects via a different macromolecular target(s) in each parasite. For FN-27, molecular dynamics (MD) simulations were performed to gain insights into the stability of its final complexes with both proteases within 200 ns, and the parameters RMSD, RMSF, R g , and SASA were determined, through which it was verified that FN-27 adopts various binding modes in the catalytic site for both proteases, corroborating our experimental data. MM/PBSA calculations suggested that the most relevant stabilizing interactions for the complex formation were van der Waals interactions. Also, it was noted that the binding energy (Δ E MM ) for Tbr CATL is more favorable than for CRZ, again corroborating the enzymatic inhibition assays. Overall, the data generated will be useful in developing novel natural-product-based inhibitors targeting both cysteine proteases.
This study evaluated the effects of 2-amino-thiophene derivatives on the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and their possible mechanisms of action. Initially, ...we evaluated the antileishmanial activity of ten 2-amino-thiophene derivatives on promastigote and axenic amastigote forms of Leishmania amazonensis and their cytotoxicity against murine macrophages and human red blood cells. Three promising compounds were selected for studies of the cell death process using flow cytometry analysis and a DNA fragmentation assay. The effects of the compounds were assessed on intramacrophagic amastigotes, and the modulation of cytokine and NO production was investigated. All thiophene derivatives showed antileishmanial activity against promastigotes and axenic amastigotes with less toxicity for murine macrophages and human red blood cells. The best values were obtained for compounds containing a lateral indole ring. Docking studies suggested that these compounds played an important role in inhibiting trypanothione reductase (TryR) activity. The selected compounds SB-200, SB-44, and SB-83 induced apoptosis in promastigotes involving phosphatidylserine externalization and DNA fragmentation in a pattern similar to that observed for the positive control. Additionally, SB-200, SB-44, and SB-83 significantly reduced the infection index of macrophages by the parasites; for compounds SB-200 and SB-83 this reduction was associated with increased TNF-α, IL-12, and NO levels. This study demonstrated the effective and selective action of 2-amino-thiophene derivatives against L. amazonensis, resulting in apoptosis-like cell death and immunomodulation in vitro. The results suggest that they are promising compounds for the development of new leishmanicidal drugs.
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•10 thiophene derivatives showed antileishmanial activity in vitro to Leishmania amazonensis.•All thiophenes exhibited selectivity indexes (SI) greater than reference drugs.•Selected compounds (SB-200, SB-44, and SB-83) induce apoptosis in promastigotes forms.•SB-200, SB-44, and SB-83 reduced the infection index of macrophages by L. amazonensis.•SB-200, and SB-83 stimulated TNF-α, IL-12, and NO production in macrophages infected.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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