ABSTRACT
The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Naphthoquinones , Humans , Female , MCF-7 Cells , Reactive Oxygen Species/metabolism , Triazoles/pharmacology , Naphthoquinones/pharmacology , AMP-Activated Protein Kinases , Cell Proliferation , Apoptosis , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Drug Screening Assays, AntitumorABSTRACT
The pathogenic complexity of Alzheimer's disease (AD) demands the development of multitarget-directed agents aiming at improving actual pharmacotherapy. Based on the cholinergic hypothesis and considering the well-established role of butyrylcholinesterase (BuChE) in advanced stages of AD, the chemical structure of the acetylcholinesterase (AChE) inhibitor drug donepezil (1) was rationally modified for the design of new N-benzyl-piperidine derivatives (4a-d) as potential multitarget-direct AChE and BuChE inhibitors. The designed analogues were further studied through the integration of in silico and in vitro methods. ADMET predictions showed that 4a-d are anticipated to be orally bioavailable, able to cross the blood-brain barrier and be retained in the brain, and to have low toxicity. Computational docking and molecular dynamics indicated the formation of favorable complexes between 4a-d and both cholinesterases. Derivative 4a presented the lowest binding free energy estimation due to interaction with key residues from both target enzymes (-36.69 ± 4.47 and -32.23 ± 3.99 kcal/mol with AChE and BuChE, respectively). The in vitro enzymatic assay demonstrated that 4a was the most potent inhibitor of AChE (IC50 2.08 ± 0.16 µM) and BuChE (IC50 7.41 ± 0.44 µM), corroborating the in silico results and highlighting 4a as a novel multitarget-directed AChE/BuChE inhibitor.
Subject(s)
Alzheimer Disease , Butyrylcholinesterase , Humans , Butyrylcholinesterase/metabolism , Butyrylcholinesterase/therapeutic use , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/therapeutic use , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Piperidines/pharmacology , Piperidines/therapeutic use , Structure-Activity Relationship , Molecular Docking SimulationABSTRACT
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the latest class of drugs approved to treat type 2 DM (T2DM). Although adverse effects are often caused by a metabolite rather than the drug itself, only the safety assessment of disproportionate drug metabolites is usually performed, which is of particular concern for drugs of chronic use, such as SGLT2i. Bearing this in mind, in silico tools are efficient strategies to reveal the risk assessment of metabolites, being endorsed by many regulatory agencies. Thereby, the goal of this study was to apply in silico methods to provide the metabolites toxicity assessment of the SGLT2i. Toxicological assessment from SGLT2i metabolites retrieved from the literature was estimated using the structure and/or statistical-based alert implemented in DataWarrior and ADMET predictorTM softwares. The drugs and their metabolites displayed no mutagenic, tumorigenic or cardiotoxic risks. Still, M1-2 and M3-1 were recognized as potential hepatotoxic compounds and M1-2, M1-3, M3-1, M3-2, M3-3 and M4-3, were estimated to have very toxic LD50 values in rats. All SGLT2i and the metabolites M3-4, M4-1 and M4-2, were predicted to have reproductive toxicity. These results support the awareness that metabolites may be potential mediators of drug-induced toxicities of the therapeutic agents.
Subject(s)
Sodium-Glucose Transporter 2 Inhibitors , Animals , Rats , Risk Assessment , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/toxicityABSTRACT
Sildenafil is a potent selective inhibitor of phosphosdiesterase-5 previously used in erectile dysfunction and subsequently approved in 2005 for pulmonary arterial hypertension treatment. Since oral administration of sildenafil shows pharmacokinetic problems with mean absolute bioavailability of 41%, the goal of this work was to develop a novel sildenafil self-emulsifying drug delivery system (SEDDS) for oral absorption improvement and management of dosage. One pharmaceutical solution and four SEDDS containing sildenafil were successfully obtained and SEDDS formed O/W nanoemulsion with droplet size less than 300 nm. The stability studies evidenced that the SEDDS containing 3.3% w/w of sildenafil yielded the best results. The safety of 2-pyrrolidone/isobutanol in oral formulations was assessed in mice and no lethality was achieved in the placebo groups with LD50 of 490 mg/Kg for SEDDS II-3.3, suggesting it as a safe excipient for humans. Therewithal, in silico studies using PBPK models provided the pharmacokinetic profile of sildenafil SEDDS. Subsequently, in silico evaluation indicated that the sildenafil SEDDS droplet size influenced its bioavailability, enhancing absorption, assuring a good pharmacokinetic profile. These findings suggest that the formulations developed here presented the potential to enhance drug oral absorption with the possibility to control drug dosage as they are liquid pharmaceutical formulations.
Subject(s)
Pulmonary Arterial Hypertension , Animals , Chemistry, Pharmaceutical , Drug Delivery Systems , Emulsions , Humans , Mice , Sildenafil CitrateABSTRACT
Inhibition of Leishmania arginase leads to a decrease in parasite growth and infectivity and thus represents an attractive therapeutic strategy. We evaluated the inhibitory potential of selected naturally occurring phenolic substances on Leishmania infantum arginase (ARGLi) and investigated their antileishmanial activity in vivo. ARGLi exhibited a Vmax of 0.28 ± 0.016 mM/min and a Km of 5.1 ± 1.1 mM for L-arginine. The phenylpropanoids rosmarinic acid and caffeic acid (100 µM) showed percentages of inhibition of 71.48 ± 0.85% and 56.98 ± 5.51%, respectively. Moreover, rosmarinic acid and caffeic acid displayed the greatest effects against L. infantum with IC50 values of 57.3 ± 2.65 and 60.8 ± 11 µM for promastigotes, and 7.9 ± 1.7 and 21.9 ± 5.0 µM for intracellular amastigotes, respectively. Only caffeic acid significantly increased nitric oxide production by infected macrophages. Altogether, our results broaden the current spectrum of known arginase inhibitors and revealed promising drug candidates for the therapy of visceral leishmaniasis.
Subject(s)
Antiprotozoal Agents/pharmacology , Arginase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Leishmania infantum/drug effects , Phenols/pharmacology , Animals , Antiprotozoal Agents/chemistry , Arginase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Leishmania infantum/enzymology , Leishmania infantum/growth & development , Macrophages/drug effects , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Phenols/chemistry , RAW 264.7 Cells , Structure-Activity RelationshipABSTRACT
Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC50 for KLK1 The most active compound (10) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Kallikreins/antagonists & inhibitors , Peptidomimetics/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Kallikreins/metabolism , Models, Molecular , Molecular Structure , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Structure-Activity RelationshipABSTRACT
Leishmaniasis are diseases caused by parasites of the genus Leishmania and transmitted to humans by the bite of infected insects of the subfamily Phlebotominae. Current drug therapy shows high toxicity and severe adverse effects. Recently, two oligopeptidases (OPBs) were identified in Leishmania amazonensis, namely oligopeptidase B (OPB) and oligopeptidase B2 (OPB2). These OPBs could be ideal targets, since both enzymes are expressed in all parasite lifecycle and were not identified in human. This work aimed to identify possible dual inhibitors of OPB and OPB2 from L. amazonensis. The three-dimensional structures of both enzymes were built by comparative modelling and used to perform a virtual screening of ZINC database by DOCK Blaster server. It is the first time that OPB models from L. amazonensis are used to virtual screening approach. Four hundred compounds were identified as possible inhibitors to each enzyme. The top scored compounds were submitted to refinement by AutoDock program. The best results suggest that compounds interact with important residues, as Tyr490, Glu612 and Arg655 (OPB numbers). The identified compounds showed better results than antipain and drugs currently used against leishmaniasis when ADMET in silico were performed. These compounds could be explored in order to find dual inhibitors of OPB and OPB2 from L. amazonensis.
Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Leishmania/enzymology , Protozoan Proteins/metabolism , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/pharmacology , Binding Sites , Computer Simulation , Databases, Factual , Gene Expression Regulation, Enzymologic , Models, Molecular , Protein Binding , Protein Conformation , Protozoan Proteins/genetics , Serine Endopeptidases/genetics , SoftwareABSTRACT
Herpes simplex virus infections have been described in the medical literature for centuries, yet the the drugs available nowadays for therapy are largely ineffective and low oral bioavailability plays an important role on the inefficacy of the treatments. Additionally, the details of the inhibition of Herpes Virus type 1 are still not fully understood. Studies have shown that several viruses encode one or more proteases required for the production new infectious virions. This study presents an analysis of the interactions between HSV-1 protease and benzoxazinone derivatives through a combination of structure-activity relationships, comparative modeling and molecular docking studies. The structure activity relationship results showed an important contribution of hydrophobic and polarizable groups and limitations for bulky groups in specific positions. Two Herpes Virus type 1 protease models were constructed and compared to achieve the best model which was obtained by MODELLER. Molecular docking results pointed to an important interaction between the most potent benzoxazinone derivative and Ser129, consistent with previous mechanistic data. Moreover, we also observed hydrophobic interactions that may play an important role in the stabilization of inhibitors in the active site. Finally, we performed druglikeness and drugscore studies of the most potent derivatives and the drugs currently used against Herpes virus.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzoxazines/chemistry , Benzoxazines/pharmacology , Herpesvirus 1, Human/drug effects , Herpesvirus 1, Human/enzymology , Models, Molecular , Peptide Hydrolases/chemistry , Binding Sites , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Conformation , Molecular Docking Simulation , Molecular Weight , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protein Binding , Structure-Activity RelationshipABSTRACT
As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor/drug effects , Cell Membrane/drug effects , Chemistry Techniques, Synthetic , Computer Simulation , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Erythrocytes/drug effects , Hemolytic Agents/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Molecular Docking Simulation , Molecular Structure , Quinolones/chemistry , Stomach Neoplasms/drug therapyABSTRACT
AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (E(LUMO)-E(HOMO)), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Diterpenes/chemistry , Diterpenes/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Binding Sites , HIV-1/drug effects , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Molecular Docking Simulation/methods , Structure-Activity RelationshipABSTRACT
The increased use of agrochemicals raises concerns about environmental, animal, and mainly human toxicology. The development of New Approach Methodologies (NAMs) for toxicological risk assessment including new in vitro tests and in silico protocols is encouraged. Although agrochemical mutagenicity testing is well established, a complementary alternative approach may contribute to increasing reliability, with the consequent reduction of false-positive results that lead to unnecessary use of animals in follow-up in vivo testing. Additionally, it is unreasonable to underestimate the phototoxic effects of an accidental dermal exposure to agrochemicals during agricultural work or domestic application in the absence of adequate personal protection equipment, especially in terms of photomutagenicity. In this scenario, we addressed the integration of in vitro and in silico techniques as NAMs to assess the mutagenic and phototoxic potential of agrochemicals. In the present study we used the yno1 S. cerevisiae strain as a biomodel for in vitro assessment of agrochemical mutagenicity, both in the absence and in the presence of simulated sunlight. In parallel, in silico predictions were performed using a combination of expert rule-based and statistical-based models to assess gene mutations and phototoxicity. None of the tested agrochemicals showed mutagenic potential in the two proposed approaches. The Gly and 2,4D herbicides were photomutagenic in the in vitro yeast test despite the negative in silico prediction of phototoxicity. Herein, we demonstrated a novel experimental approach combining both in silico and in vitro experiments to address the complementary investigation of the phototoxicity and (photo)mutagenicity of agrochemicals. These findings shed light on the importance of investigating and reconsidering the photosafety assessment of these products, using not only photocytotoxicity assays but also photomutagenicity assays, which should be encouraged.
Subject(s)
Mutagens , Saccharomyces cerevisiae , Humans , Animals , Agrochemicals/toxicity , Reproducibility of Results , Risk Assessment , In Vitro TechniquesABSTRACT
Benzophenone derivatives (BZP), an important class of organic UV filters, are widely used in sunscreen products due to their ability to absorb in the UVA and UVB ranges. The structural, electronic, and spectral properties of BZP derivatives have been studied by density functional theory (DFT) and time-dependent DFT (TD-DFT) methods. DFT/B3LYP with the 6-31G(d) basis set is an accurate method for optimizing the geometry of BZPs. The absorption maxima obtained from the TD-DFT calculations in a vacuum were in agreement with the experimental absorption bands and showed that the main electronic transitions in the UVA/UVB range present π â π* character, the major transition being HOMO â LUMO. The oscillator strength seems to increase in the presence of disubstitution at the para position. For protic substituents, the position appears to be related to the absorption band. Absorption in the UVB range occurs in the presence of para substitution, whereas ortho substitution leads to absorption in the UVA spectral region. The obtained results provide some features for BZP derivatives that can be useful for customizing absorption properties (wavelengths and intensities) and designing new BZP derivatives as sunscreens.
Subject(s)
Benzophenones/chemistry , Models, Molecular , Quantum Theory , Electronics , Ultraviolet RaysABSTRACT
Leishmaniasis is a neglected disease responsible for about 56,000 deaths every year. Despite its importance, there are no effective, safe and proper treatments for leishmaniasis due to strain resistance and/or drug side-effects. In this work we report the synthesis, molecular modeling, cytotoxicity and the antileishmanial profile of a series of 4-(1H-pyrazol-1-yl)benzenesulfonamides. Our experimental data showed an active profile for some compounds against Leishmania infantum and Leishmania amazonensis. The profile of two compounds against L. infantum was similar to that of pentamidine, but with lower cytotoxicity. Molecular modeling evaluation indicated that changes in electronic regions, orientation as well as lipophilicity of the derivatives were areas to improve the interaction with the parasitic target. Overall the compounds represent feasible prototypes for designing new molecules against L. infantum and L. amazonensis.
Subject(s)
Leishmania infantum/drug effects , Leishmania mexicana/drug effects , Sulfonamides/pharmacology , Trypanocidal Agents/pharmacology , Animals , Cell Survival/drug effects , Cells, Cultured , Drug Evaluation, Preclinical , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/physiology , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Conformation , Pentamidine/pharmacology , Quantum Theory , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistryABSTRACT
A broad-spectrum antibiotic therapy has led to medical complications and emergence of multiresistant bacteria including Enterococcus faecalis. In this study, we designed, synthesized, and evaluated the antibacterial activity of 13 nor-ß-lapachone derivatives against a drug resistant E. faecalis strain. Two triazole substituted compounds (1e = 8 µg/ml and 1c = 16 µg/ml) and the non-substituted derivative (1a = 8 µg/ml) were promising compared to chloramphenicol (12 µg/ml), an antibiotic currently available in the market. We also performed a structure-activity relationship analysis using a molecular modeling approach that pointed the low HOMO energy values; HOMO density concentrated on the nor-ß-lapachone ring, lipophilicity, solubility and number HBA as important stereoelectronic features for the antibacterial profile. In addition the triazole compounds presented low theoretical toxicity profile, and drug-score higher than commercial antibiotics also fulfilling the Lipinski "Rule of Five", which pointed them as promising candidates for further studies in infections caused by multiresistant E. faecalis hospital strains.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Naphthoquinones/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Enterococcus faecalis/isolation & purification , Gram-Positive Bacterial Infections/microbiology , Humans , Microbial Sensitivity Tests , Naphthoquinones/chemistry , Naphthoquinones/toxicity , Structure-Activity RelationshipABSTRACT
In this study we compared the effects of naphthoquinones (α-lapachone, ß-lapachone, nor-ß-lapachone and Epoxy-α-lap) on growth of Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed ß-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-ß-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. ß-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and ß-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that ß-lapachone and Epoxy-α-lap compounds may inhibit T. cruzi epimastigotes growth by affecting T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds.
Subject(s)
Anti-Infective Agents/pharmacology , Naphthoquinones/pharmacology , Peptide Hydrolases/drug effects , Protease Inhibitors/pharmacology , Trypanosoma cruzi/drug effects , Animals , Chlorocebus aethiops , Cysteine Endopeptidases , Cysteine Proteinase Inhibitors/pharmacology , Leucine/analogs & derivatives , Leucine/pharmacology , Peptide Hydrolases/metabolism , Protozoan Proteins/antagonists & inhibitors , Trypanosoma cruzi/enzymology , Trypanosoma cruzi/growth & development , Vero CellsABSTRACT
With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2',4',6'- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.
Subject(s)
Antiprotozoal Agents/therapeutic use , Chalcone/metabolism , Chalcone/pharmacology , Cytosol/drug effects , Leishmania/drug effects , Peroxidases/antagonists & inhibitors , Protozoan Proteins/antagonists & inhibitors , Animals , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/pharmacology , Cells, Cultured , Chalcone/administration & dosage , Chalcone/analogs & derivatives , Cytosol/enzymology , Cytosol/parasitology , Drug Discovery , Humans , Leishmania/classification , Leishmaniasis/drug therapy , Leishmaniasis/parasitology , Macrophages/drug effects , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Molecular Docking Simulation , Peroxidases/metabolism , Protozoan Proteins/metabolismABSTRACT
Tropical infectious diseases cause millions of deaths every year in developing countries, with about half of the world population living at risk. Mayaro virus (MAYV) is an emerging arbovirus that causes Mayaro fever, which is characterized by fever, headache, diarrhea, arthralgia, and rash. These symptoms can be clinically indistinguishable from other arboviruses, such as Dengue, Zika, and Chikungunya, which makes the diagnosis and treatment of the disease more difficult. Though, the Mayaro virus is a potential candidate to cause large-scale epidemics on the scale of ZIKV and CHIKV. Despite this, there is no licensed vaccine or antiviral for the treatment of Mayaro fever and most arboviruses, so the design and development of candidates for antiviral drugs are urgently needed. In this context, this mini-review aims to provide an overview of studies of anti-MAYV derivatives and highlight the importance of the discovery and development of promising drug candidates for Mayaro fever.
Subject(s)
Alphavirus Infections/drug therapy , Alphavirus/drug effects , Alphavirus/physiology , Antiviral Agents/pharmacology , Drug Discovery , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , HumansABSTRACT
Arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea, acting as a key enzyme in the biosynthesis of polyamines. Leishmania growth and survival is dependent on polyamine biosynthesis; therefore, inhibition of Leishmania arginase may be a promising therapeutic strategy. Here, we evaluated a series of thirty-six chalcone derivatives as potential inhibitors of Leishmania infantum arginase (LiARG). In addition, the activity of selected inhibitors against L. infantum parasites was assessed in vitro. Seven compounds exhibited LiARG inhibition above 50% at 100 µM. Among them, compounds LC41, LC39, and LC32 displayed the greatest inhibition values (72.3 ± 0.3%, 71.9 ± 11.6%, and 69.5 ± 7.9%, respectively). Molecular docking studies predicted hydrogen bonds and hydrophobic interactions between the most active chalcones (LC32, LC39, and LC41) and specific residues from LiARG's active site, such as His140, Asn153, His155, and Ala193. Compound LC32 showed the highest activity against L. infantum promastigotes (IC50 of 74.1 ± 10.0 µM), whereas compounds LC39 and LC41 displayed the best results against intracellular amastigotes (IC50 of 55.2 ± 3.8 and 70.4 ± 9.6 µM, respectively). Moreover, compound LC39 showed more selectivity against parasites than host cells (macrophages), with a selectivity index (SI) of 107.1, even greater than that of the reference drug Fungizone®. Computational pharmacokinetic and toxicological evaluations showed high oral bioavailability and low toxicity for the most active compounds. The results presented here support the use of substituted chalcone skeletons as promising LiARG inhibitors and antileishmanial drug candidates.
ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 µM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 µM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design.
Subject(s)
4-Quinolones/pharmacology , Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Ribonucleosides/pharmacology , 4-Quinolones/chemical synthesis , 4-Quinolones/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Dose-Response Relationship, Drug , Drug Design , HIV Reverse Transcriptase/metabolism , HIV-1/metabolism , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Ribonucleosides/chemical synthesis , Ribonucleosides/chemistry , Structure-Activity RelationshipABSTRACT
Current drugs for treating leishmaniasis are still associated with significant toxicity and failure rates. Thus, new effective and less toxic antileishmanial agents are still in need. Herein, we tested a series of sulfonamide 4-methoxychalcone derivatives against L. amazonensis promastigote and amastigote forms to identify its antileishmanial profile against this species compared to L. braziliensis. In addition, we used molecular modeling tools to determine stereoelectronic features that may lead to the antileishmanial profile. Interestingly, all tested compounds were able to affect L. amazonensis promastigote form in a concentration-dependent manner and with low cytotoxicity, except for derivative 3g. However, our results showed that compound 3f (para-Cl) presents the best profile against both L. amazonensis forms (promastigote and amastigote), differently from that observed for L. braziliensis, when compound 3i was the most active. Structure-activity relationship (SAR) analysis of these derivatives pointed molecular volume, HOMO density, and conformational aspects as important characteristics for parasitic profile. Overall, sulfonamide 4-methoxychalcone derivatives may be pointed out not only as lead compounds for treating leishmaniasis (i.e., 3f) but also as experimental tools presenting parasite-selectivity (i.e., 3i).