Search

An approach combining CoMFA and HQSAR methods was used to describe QSAR models for a series of cruzain inhibitors having the acylhydrazide framework. A CoMFA study using two alignment orientations (I and II), three different probe atoms and changes of the lattice spacing (1 and 2 A˚) was performed. Alignment II and an sp3 probe carbon atom yielded good cross-validation (q2=0.688) employing lattice spacing of 1 A˚. The best HQSAR model was generated using atoms, bond, and connectivity as fragment distinction and fragment size default (4–5) showing similar cross-validated value of CoMFA (q2=0.689). Based upon the information derived from CoMFA and HQSAR, we have identified some key features that may be used to design new acylhydrazide derivatives that may be more potent cruzain inhibitors. [Copyright &y& Elsevier]

COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro. [ABSTRACT FROM AUTHOR]

Aims: To develop paediatric physiologically based pharmacokinetic modelling (PBPK) models of semaglutide to estimate the pharmacokinetic profile for subcutaneous injections in children and adolescents with healthy and obese body weights. Methods: Pharmacokinetic modelling and simulations of semaglutide subcutaneous injections were performed using the Transdermal Compartmental Absorption & Transit model implemented in GastroPlus v.9.5 modules. A PBPK model of semaglutide was developed and verified in the adult population, by comparing the simulated plasma exposure with the observed data, and further scaled to the paediatric populations with normal and obese body weight. Results: The semaglutide PBPK model was successfully developed in adults and scaled to the paediatric population. Our paediatric PBPK simulations indicated a significant increase in maximum plasma concentrations for the 10–14 years' paediatric population with healthy body weights, which was higher than the observed values in adults at the reference dose. Since gastrointestinal adverse events are related to increased semaglutide concentrations, peak concentrations outside the target range may represent a safety risk for this paediatric age group. Besides, paediatric PBPK models indicated that body weight was inversely related to semaglutide maximum plasma concentration, corroborating the consensus on the influence of body weight on semaglutide PK in adults. Conclusion: Paediatric PBPK was successfully achieved using a top‐down approach and drug‐related parameters. The development of unprecedented PBPK models will support paediatric clinical therapy for applying aid‐safe dosing regimens for the paediatric population in diabetes treatment. [ABSTRACT FROM AUTHOR]

Cancer remains among the world's top devastating diseases, with millions of lives been affected each year. Conventional anticancer therapies are often far from ideal due to non-selective biodistribution. Therefore, the carbon nanotube (CNT) has been developed as a drug carrier for targeting specific cancer cells. In this work, we applied computer modeling approaches to investigate the interactions of single-wall carbon nanotube (SWCNT) with three different anticancer drugs: doxorubicin (DOX), Bendamustine (BEN), and Carmustine (CAR). Here we find physicochemical characteristics from the ligands that can contribute to a higher affinity towards the CNT, such as the presence of halogen substituents and the positively charged cation. On the other hand, the presence of anions groups, such as carboxylate, can decrease the interaction of the ligands and CNT. The binding free energy results indicate the SWCNT(15,15) with a diameter of 20.3 Å as the most favorable for encapsulating drugs ranging from 12 to 39 heavy atoms. The basic knowledge obtained from this study is expected to contribute to the molecular understanding of drug-loaded SWCNT for the development of a more efficiently anticancer drug carrier. [Display omitted] • Simulations were applied to investigate the single-wall carbon nanotube as a drug carrier. • Halogen substituents and charged cations contribute to a higher affinity towards the carbon nanotube. • Anions groups can decrease the interaction with carbon nanotube. • Carbon nanotube with a diameter of 20.3 Å was the most favorable for encapsulating drugs ranging from 12 to 39 heavy atoms. [ABSTRACT FROM AUTHOR]

Abstract: Antibacterial resistance is a complex problem that contributes to health and economic losses worldwide. The Staphylococcus epidermidis is an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices. Currently, there are several resistant strains including S. epidermidis that became an important medical issue mainly in hospital environment. In this work, we report the biological and theoretical evaluations of a 4-(arylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acids series (1, 1a–m) and the comparison with a new isosteric ring nucleus series, 4-(arylamino)thieno[2,3-b]pyridine-5-carboxylic acids derivatives (2, 2a–m). Our results revealed the 1H-pyrazolo[3,4-b]pyridine derivatives significant antibacterial activity against a drug-resistant S. epidermidis clinical strain in contrast to the thieno[2,3-b]pyridine series. The minimal inhibitory concentration (MIC) of the most active derivatives (1a, 1c, 1e, and 1f) against S. epidermidis was similar to that of oxacillin and twofold better than chloramphenicol. Interestingly, the position of the functional groups has a great impact on the activity as observed in our structure–activity relationship (SAR) study. The SAR of 1H-pyrazolo[3,4-b]pyridine derivatives shows that the highest inhibitory activity is observed when the meta position is occupied by electronegative substituents. The molecular modeling analysis of frontier molecular orbitals revealed that the LUMO density is less intense in meta than in ortho and para positions for both series (1 and 2), whereas HOMO density is overconcentrated in 1H-pyrazolo[3,4-b]pyridine ring nucleus compared to the thieno[2,3-b]pyridine system. The most active derivatives of series 1 were submitted to in silico ADMET screening, which confirmed these compounds as potential antibacterial candidates. [Copyright &y& Elsevier]

In this paper we described the synthesis of the cis-2-azabicyclo[3.3.0]octane derivative (5b) employing highly diastereoselective mercury(II)-mediated intramolecular amino-cyclization, followed by reductive demercuration of ethyl erythro-1-allyl-2-amino-1-cyclopentanecarboxylate (7b). Molecular dynamic studies were performed in order to find a suitable explanation of the diastereoselectivity of azamercuration in comparison with corresponding oxymercuration process. [Copyright &y& Elsevier]

Among the members of purinergic receptors, the family P2X of ionotropic proteins has the ion channel subtype P2X7 that show in studies to be an important molecular target for new drugs. The activity of human P2X7 receptor (hP2X7r) in the body, due to its pro-inflammatory function, can trigger physiological disorders related to chronic inflammatory processes, leading to neural degeneration, neuropathic pain and chronic pain. Recently, two series of promising new inhibitors of the hP2X7r ion channel have been reported. One series consisted of naphthoquinone derivatives and the other composed of triazole derivatives. The main objective of this study was to understand the binding mode differences between the hit compounds of each series and compare them to the native ligand ATP. The hP2X7r ion channel and membrane lipid models were prepared in order to allow study the appropriate protein molecular dynamics. Molecular modeling and molecular dynamics simulation approaches were applied in order to obtain atomistic and molecular details that are involved in intermolecular interactions. Both compounds AN-04 and 9d seem to have affinity to binding in the hP2X7r pore area according to molecular dynamics simulations results. The naphthoquinone derivative AN-04 demonstrated a binding free energy 7.68 fold larger than triazole derivative 9d and 3.8 fold lower than native ligand ATP. These results indicate that compound AN-04 might be a promising lead compound for the development of a novel selective hP2X7r inhibitor. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Abstract Olive leaves contain higher amount of polyphenols than olive oil and represent a waste product from olive harvest and pruning of olive trees. The most abundant compound in olive leaves is oleuropein. Benefits of the topical application of olive leaves extract were previously reported, but little information is available on its photoprotective potential and the result of the association of this extract with organic UV filters in topical sunscreen formulations. The olive leaves extract photoprotective potential is less explored for both oral and topical photoprotection in comparison with other plants extracts and polyphenols, such as Polypodium leucotomos extract and resveratrol. There are increasing efforts towards developing more efficient sunscreens and a photoprotection assessement along with a better understanding of the photochemistry of naturally occurring sunscreens could aid the design of new and improved commercial sunscreen formulations. This study was designed to investigate the photoprotective potential of olive leaves extract standardized for oleuropein performing a set of in vitro and in silico tools as an innovative approach, highlighting yeast assays, in vitro Sun Protection Factor (SPF) and molecular modelling studies of UV absorption. This study supports the use of olive leaves extract for photoprotection, as an effective photoprotective, anti-mutagenic and antioxidant active, also showing a synergistic effect in association with UV filters with an improvement on in vitro SPF of sunscreen formulations. Graphical Abstract Unlabelled Image Highlights • Olive leaves extract standardized to oleuropein is investigated for sunscreens. • OLE increases photoprotection in yeasts ogg1 mutant exposed upon SSL. • OLE show anti-mutagenic effect in yeasts ogg1 mutant exposed upon SSL. • In vitro SPF improvement due to the synergism of OLE and UV filters. • Theoretical studies of UV absorption mechanisms of oleuropein and resveratrol. [ABSTRACT FROM AUTHOR]

[Display omitted] • New twenty-three hybrids bisnaphthoquinone x 1,2,3-1 H -triazole were developed. • All compounds were screened against breast cancer cell lines MCF-7 and MDA-MB-231. • Some compounds presented as potential new drugs for cancer treatment. • Two of them (12g and 12h) two of them were selective with low toxicity. • 12g and 12h are novel AMPK activators presenting selective antitumor effects. 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 1,2,3-1 H -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. [ABSTRACT FROM AUTHOR]

Investigations on the photoprotection mechanisms of molecular sunscreens is critical to developing more efficacious sunscreen products. Molecular modeling has proved to be very helpful in understanding intrinsic properties of molecules that protect our skin from the harmful rays of the sun and gathering useful features to developing improved sunscreens. Herein the investigation focuses on the stereoelectronic properties related to photoprotection mechanisms of triazine and benzotriazole derivatives, important compound classes based on their physical-chemical properties, such as resonance and ultraviolet (UV) broad spectrum absorption (UVA and UVB). The method proved to be a valuable tool to reproduce the experimental UV absorption of a set of triazine and benzotriazole derivatives with compromise between the accuracy and the computational speed. All calculations were carried out considering only the isolated UV filter (in vacuum) and have provided a qualitative prediction and interpretation of absorption properties. The lowest band gap energy (E bg ), highest chemical potential (μ) and lowest chemical hardness (η) values were observed to the orthohydroxy substituted derivatives that are able to undergo excited-state proton transfer (ESPT), supporting the UVA absorption and resulting in excellent photostability. [ABSTRACT FROM AUTHOR]

The preparation of new biocompatible polymer systems could accelerate processes underlying guided bone tissue regeneration (GBR) by acting as adjuvants. Here, different reaction conditions were investigated to engineer nanocomposites based on chitosan and sodium montimorilonite (Na-Mt) that can be used to generate biocompatible membranes. The goal was a balanced combination of flexibility and tensile strength for use in orthopedic and periodontal surgical procedures for improved GBR. The execution of different experimental protocols aimed to control the polymer intercalation process inside the Na-Mt lamellae, and to avoid their exfoliation, by varying its concentration while applying, at same time, ultrasonic energy as a pretreatment. To increase the therapeutic efficacy of the membranes formed, sodium alendronate was included in the compositions as well as plasticizers to optimize their mechanical and physical-chemical properties. All membranes were analyzed by powder x-ray diffraction, nuclear magnetic resonance, differential scanning calorimetry and thermogravimetric analysis, as well as high performance chromatography to characterize the sodium alendronate content. Surface roughness, water absorption (swelling) and tensile strength were evaluated by scanning electron microscope and profilometry. As a model for human osteoblasts, the proliferation of Saos-2 cells was measured by colorimetric assays and microscopy to assess the potential performance of the membranes in GBR. Membranes with improved mechanical and physical-chemical properties along with excellent biocompatibility could be generated from 33% sodium montmorillonite (w/w) intercalated with chitosan and containing sodium alendronate, glycerol (20% [w/w]) and Labrasol® (3% [w/w]) that also supported the induction of Saos-2 cell proliferation and differentiation, exhibiting potential to develop a novel biomaterial device for GBR [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) account for over 17 million deaths globally each year, with atherosclerosis as the underlying cause of most CVDs. Herein we describe the synthesis and in vitro mechanistic evaluation of novel N ’-benzylidene-carbohydrazide-1 H -pyrazolo[3,4- b ]pyridines ( 3 - 22 ) designed as non-anionic antiplatelet agents and presenting a 30-fold increase in potency compared to aspirin. The mechanism underlying their antiplatelet activity was elucidated by eliminating potential targets through a series of in vitro assays including light transmission aggregometry, clot retraction, and quantitative ELISA, further identifying the reduction in biosynthesis of thromboxane B2 as their main mechanism of action. The intrinsic fluorescence of the compounds permits their binding to platelet membranes to be readily monitored. In silico structure-activity relationship, molecular docking and dynamics studies support the biological profile of the series revealing the molecular basis of their activity and their potential as future molecular therapeutic agents. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles. [ABSTRACT FROM AUTHOR]

The potential of antioxidants as tools for decreasing the incidence of diseases, including cardiovascular events, is of growing interest. Some antioxidants (e.g. vitamin E and acetyl-salicylic acid) have been described as effective on cardiovascular diseases with mechanisms that differ from other scavenging agents. Currently, vitamin C is used to open occluded long-term central venous catheters, which avoids the process of reinserting a new one and injuring the patient. In this work, we investigated the vitamin C antihemostatic profile by evaluating its effects on the coagulation process. We used different assays, including prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT) and ancrod time tests. We also examined the overall pH disturbance caused by vitamin C at different concentrations and its effect on the thrombin-initiated fibrin polymerization assay. Our results revealed a significant anticoagulant activity of vitamin C at high plasma concentrations (surpassing the normal 100 μmol/L ratio) in a cell-independent mechanism. Our results suggest that vitamin C may affect blood coagulation by a direct impairment of fibrin assembly and further formation of a cohesive clot microstructure. This study supports the literature that points to the antihemostatic ability of antioxidant agents, and clarifies the mechanism of vitamin C in opening occluded long-term central venous catheters. [ABSTRACT FROM AUTHOR]

• Compounds 15a-k were synthesized as antitumoral agents. • 15c, 15e , 15g, and 15k showed significant cytotoxicity. • 15c, g , and k increased the levels of reactive species and superoxide ions. • In silico toxicity screening showed that 15g presented low hepatotoxicity risk. • 15g is a potential candidate to optimize for the development of anticancer agents. Breast cancer is the leading cause of cancer death in women. Although the available treatments are efficient, cancer cells promptly develop resistance to different drugs, leading to disease relapse and promoting tumor progression. Here, novel 4-oxoquinoline-3-carboxamide acyclonucleoside phosphonate hybrids were synthesized as antitumoral agents, and in silico toxicity screening were performed. Derivatives 15c, 15e , 15g, and 15k showed significant cytotoxicity where 15c induces the most considerable loss of cell viability through the apoptotic process, while 15k induces cell death by necrosis. All compounds, except 15e , induced the production of OH- and NO, besides increasing the levels of superoxide ions. In silico toxicity studies showed that 15g presented low hepatotoxicity risk and probability as BCRP substrate. These findings point out that derivative 15g is a potential candidate for an optimization program for the development of new anticancer agents. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Layered drug delivery carriers are current targets of nanotechnology studies since they are able to accommodate pharmacologically active substances and are effective at modulating drug release. Sodium montmorillonite (Na-MMT) is a clay that has suitable properties for developing new pharmaceutical materials due to its high degree of surface area and high capacity for cation exchange. Therefore Na-MMT is a versatile material for the preparation of new drug delivery systems, especially for slow release of protonable drugs. Herein, we describe the intercalation of several amine-containing drugs with Na-MMT so we can derive a better understanding of how these drugs molecules interact with and distribute throughout the Na-MMT interlayer space. Therefore, for this purpose nine sodium montmorillonite/amine-containing drugs complexes (Na-MMT/drug) were prepared and characterized. In addition, the physicochemical properties of the drugs molecules in combination with different experimental conditions were assessed to determine how these factors influenced experimental outcomes (e.g. increase of the interlayer spacing versus drugs arrangement and orientation). We also performed a molecular modeling study of these amine-containing drugs associated with different Na-MMT/drug complex models to analyze the orientation and arrangement of the drugs molecules in the complexes studied. Six amine-containing drugs (rivastigmine, doxazosin, 5-fluorouracil, chlorhexidine, dapsone, nystatin) were found to successfully intercalate Na-MMT. These findings provide important insights on the interlayer aspect of the molecular systems formed and may contribute to produce more efficient drug delivery nanosystems. [ABSTRACT FROM AUTHOR]

Photoprotective potential and biological consequences (mutagenic potential) of octyl-dimethyl- PABA ( ODP), titanium dioxide ( Ti O2), and montmorillonite ( MMT) upon ultraviolet B ( UVB) irradiation, alone and in different associations [physical mixtures ( PMs)], were evaluated using a Saccharomyces cerevisiae ogg1 mutant (deficient) strain. In addition, we developed and characterized a delaminated Ti O2-pillared MMT, called the Ti O2- MMT nanocomposite ( NC), which was also investigated in terms of its photoprotective and mutagenic potential. Overall, our results revealed an interesting Ti O2- MMT NC endowed with antimutagenic activity that can be associated to organic sunscreen molecule ( ODP) and still maintain its positive effect, whereas its respective PM is unable to grant antimutagenic protection against UVB. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2539-2545, 2014 [ABSTRACT FROM AUTHOR]

• Montmorillonite (MMT) may play a very crucial role in modulating drug delivery of class II drugs of biopharmaceutical classification system, such as bromopride. • Bromopride was successfully intercalated in the sodium-MMT and the complex showed sustained release during performed assays. • This new bromopride sustained-release system showed an alternative to improve its pharmacological performance in therapeutic applications. • Molecular dynamics simulations showed the bromopride interactions to the montmorillonite layer. The drug delivery systems are an important strategy of pharmaceutical technology to modulate undesirable properties, increasing efficacy, and reducing the side effects of active pharmaceutical ingredients (API). The sustained release is a type of controlled-release system that provides a suitable drug level in the blood through a slow release rate. An interesting alternative to achieve a controlled release is the application of carrier materials such as polymers, cyclodextrins, and clays. Sodium montmorillonite (Na-MMT) is a biocompatible natural clay that allows the insertion of organic compounds in interlamellar space, owing to its high cation exchange capacity and large internal surface area. Bromopride (BPD) is an aminated compound with antiemetic properties classified as class II (low solubility, high permeability) of the Biopharmaceutical Classification System (BCS). Herein, the aim of the study was the development and investigation of a drug delivery system formed by intercalation of BPD with Na-MMT. The results indicate the successful intercalation of this API with the lamellar silicate, meanwhile, there was no evidence of BPD intercalation in organic montmorillonite. The Na-MMT/BPD molecular complex exhibits a sustained release in performed assays. Molecular dynamics simulations suggested that BPD molecules interact with the montmorillonite layer through ion-dipole interactions and also between BPD molecules, forming hydrogen bonds web into montmorillonite interlayer space. The new drug delivery system showed an alternative to achieve the BPD sustained release, which may improve its pharmacological performance in therapeutic applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Recently, many efforts have been made to develop N-methyl- d-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives ( 1a- 1q), reported as N-methyl- d-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting ( R = 0.914) was able to explain 83.6% of the biological data variance ( R2 = 0.836), presented a satisfactory internal predictive ability ( Q2 = 0.609) and contained the descriptors (EHOMO, Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl- d-aspartic acid receptor antagonists. [ABSTRACT FROM AUTHOR]

Benzophenone derivatives (BZP), an important class oforganic UV filters, are widely used in sunscreen products due to theirability to absorb in the UVA and UVB ranges. The structural, electronic,and spectral properties of BZP derivatives have been studied by densityfunctional theory (DFT) and time-dependent DFT (TD-DFT) methods. DFT/B3LYPwith the 6-31G(d) basis set is an accurate method for optimizing thegeometry of BZPs. The absorption maxima obtained from the TD-DFT calculationsin a vacuum were in agreement with the experimental absorption bandsand showed that the main electronic transitions in the UVA/UVB rangepresent π → π* character, the major transitionbeing HOMO → LUMO. The oscillator strength seems to increasein the presence of disubstitution at the para position. For proticsubstituents, the position appears to be related to the absorptionband. Absorption in the UVB range occurs in the presence of para substitution,whereas ortho substitution leads to absorption in the UVA spectralregion. The obtained results provide some features for BZP derivativesthat can be useful for customizing absorption properties (wavelengthsand intensities) and designing new BZP derivatives as sunscreens. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Abstract: Tuberculosis treatment remains a challenge that requires new antitubercular agents due to the emergence of multidrug-resistant Mycobacterium strains. This paper describes the synthesis, the antitubercular activity and the theoretical analysis of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (8a–b, 8e–f, 8i–j and 8n–o) and new analogues (8c–d, 8g–h, 8l–m and 8p–q). These derivatives were synthesized in good yields and some of them showed a promising antitubercular profile. Interestingly the N-acylhydrazone (NAH) 8n was the most potent against the Mycobacterium tuberculosis H37Rv strain (MIC=2.5μg/mL) similar to or better than the current drugs on the market. The theoretical structure–activity relationship study suggested that the presence of the furyl ring and the electronegative group (NO2) as well as low lipophilicity and small volume group at R position are important structural features for the antitubercular profile of these molecules. NMR spectra, IR spectra and elemental analyses of these substances are reported. [Copyright &y& Elsevier]

Herpes simplex virus is an important human pathogen responsible for a range of diseases from mild uncomplicated mucocutaneous infections to life-threatening ones. Currently, the emergence of Herpes simplex virus resistant strains increased the need for more effective and less cytotoxic drugs for Herpes treatment. In this work, we synthesized a series of oxoquinoline derivatives and experimentally evaluated the antiviral activity against acyclovir resistant HSV-1 strain as well as their cytotoxity profile. The most active compound ( 3b), named here as Fluoroxaq-3b, showed a promising profile with a better cytotoxicity profile than acyclovir. The theoretical analysis of the structure-activity relationship of these compounds revealed some stereoelectronic properties such as lower LUMO energy and lipophilicity, besides a higher polar surface area and number of hydrogen bond acceptor groups as important parameters for the antiviral activity. Fluoroxaq-3b showed a good oral theoretical bioavailability, according to Lipinski rule of five, with a promising profile for further in vivo analysis. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones (3a–g) have been synthesized and evaluated for their in vitro antiproliferative activities against four human cancer cell lines: MDA-MB-435 (breast), HL-60 (leukemia), HCT-8 (colon) and SF-295 (central nervous system). The results showed that the compounds 3b (2-(benzo[d]thiazol-2-yl)-8-methyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) and 3c (2-(benzo[d]thiazol-2-yl)-8-bromo-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) exhibited good cytotoxicity for three cell lines with IC50 values lower than 5μg/mL. Analysis of theoretical toxicity risks have shown medium tumorigenic and irritant risks related to 3b and 3c in contrast to doxorubicin, the positive control. [Copyright &y& Elsevier]

The article provides a brief review of the structures of four proteases which include thrombin, human immunovirus (HIV)-1 protease, cruzain, and a matrix metalloproteinase. It discusses the regulation and function of the proteases and their substrates. It also cites the proteases' significant roles in human diseases and uses them as examples of the importance of proteases for the development of new treatment strategies.

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-β-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-β-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. [ABSTRACT FROM AUTHOR]

Abstract: In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-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 β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-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. β-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 β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-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. [ABSTRACT FROM AUTHOR]

Abstract: The current treatment used against envenomation by Lachesis muta venom still presents several side effects. This paper describes the synthesis, pharmacological and theoretical evaluations of new 1-arylsulfonylamino-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters (8a–f) tested against the hemolytic profile of the L. muta snake venom. Their structures were elucidated by one- and two-dimensional NMR techniques (1H, APT, HETCOR 1 J CH and nJ CH, n =2, 3) and high-resolution electrospray ionization mass spectrometry. The series of triazole derivatives significantly neutralized the hemolysis induced by L. muta crude venom presenting a dose-dependent inhibitory profile (IC50 =30−83μM) with 1-(4′-chlorophenylsulfonylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl ester (8e) being the most potent compound. The theoretical evaluation revealed the correlation of the antiophidian profile with the coefficient distribution and density map of the Highest Occupied Molecular Orbitals (HOMO) of these molecules. The elucidation of this new series may help on designing new and more efficient antiophidian molecules. [Copyright &y& Elsevier]

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). [ABSTRACT FROM AUTHOR]

Abstract: In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives. The structure–activity relationship analysis revealed some stereoelectronic properties such as LUMO energy, dipole moment, number of rotatable bonds, and of hydrogen bond donors and acceptors correlated with the potency of compounds. We also describe the importance of substituents R2 and R3 for their biological activity. Compound 2j was identified as a lead compound for future investigation due to its : (i) high activity against HIV-1, (ii) low cytotoxicity in PBMC, (iii) low toxic risks based on in silico evaluation, (iv) a good theoretical oral bioavailability according to Lipinski ‘rule of five’, (v) higher druglikeness and drug-score values than current antivirals AZT and efavirenz. [Copyright &y& Elsevier]

Abstract: This paper describes the synthesis, antiplatelet and theoretical evaluations of 10 N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (2a–j). These compounds were synthesized, characterized and screened for their in vitro antiplatelet profile against human platelet aggregation using arachidonic acid, adrenaline and ADP as agonists. Among NAH derivatives 2a–j, the compounds 2a, 2c, 2e, 2g and 2h were the most promising molecules with significant antiplatelet activity. [Copyright &y& Elsevier]

Abstract: Despite clinical importance of leishmaniasis, an infectious disease that affects 12 thousand million people in 88 countries, the treatment is still unsatisfactory due to its limited efficacy, cost expensive and undesirable side effects. Aiming to develop new antileishmanial lead compounds, we used a rational approach to synthesize a new set of sulfonamide 4-methoxychalcone derivatives (3a–3i) and evaluate the sulfonamide and methoxy moieties as promising adding-groups to chalcones. For that purpose we tested this new set against Leishmania braziliensis promastigotes and intracellular amastigotes and determined its cell toxicity profile. Interestingly all compounds presented a concentration-dependent antileishmanial profile and the benzylamino derivative (3i) showed a biological activity better than pentamidine. None of these compounds affected Trypanosoma cruzi epimastigotes, which suggests a specific antileishmanial profile. The structure–activity analysis of these sulfonamide 4-methoxychalcone derivatives pointed the molecular volume, the HOMO density concentrated in the chalcone moiety and the conformational structure of the compounds as important structural and stereoelectronic features for the antileishmanial activity. In addition, these compounds also fulfilled Lipinski rule of 5 and presented druglikeness similar to antileishmanial drugs. Altogether these results point the sulfonamide 4-methoxychalcone derivatives as potential lead compounds for designing new candidates for leishmaniasis treatment. [Copyright &y& Elsevier]

Abstract: αIIbβ3 is an integrin that is involved in platelet adhesion and aggregation. This receptor may be inhibited by cysteine-rich peptides known as disintegrins. We isolated two disintegrins from Bothrops jararaca venom called jarastatin and jararacin. We evaluated the structural characteristics and the effects on human platelet aggregation of these disintegrins. Inhibitory profiles were compared to six distinct peptides synthesized based on their RGD hairpin loop primary sequences. Both jarastatin and jararacin inhibited ADP and thrombin induction. Conversely, none of the cyclic peptides showed high-quality activity in assays induced by ADP or thrombin. We constructed homology models for all of these molecules, and theoretically evaluated their interaction with the αIIbβ3 crystal structure using a molecular modeling approach. These results support the observations that the cyclic peptides had little effects, and also reinforce the observation that residues outside the disintegrin RGD sequence are required for interactions with receptor. [Copyright &y& Elsevier]

Abstract: Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X=H, Y= p-NO2, pIC50 =4.55M) and 6l (X=F, Y= p-CN, pIC50 =4.27M) as the most potent derivatives compared to crystal violet (pIC50 =3.77M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising profile with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it. [Copyright &y& Elsevier]

Abstract: This paper describes the synthesis of several 1-benzyl-1H-1,2,3-triazoles attached to different carbohydrate templates and their in vitro inhibitory profile against HIV-1 reverse transcriptase. In addition a theoretical comparison of the most active compounds with other classical antivirals was also performed. Our results showed 2a, 2d and 2g as the most active compounds that inhibited the HIV-1 reverse transcriptase catalytic activity with cytotoxicity lower than AZT and SI higher than DDC and DDI. The overall theoretical analysis of the molecular descriptors of 2a, 2d and 2g revealed that their HOMO energy is similar to other antivirals in use (AZT, DDC, DDI and 3TC) and together with the volume may contribute for the biological profile as they may allow new interactions with the target. In fact the 1,2,3-triazole compounds presented more lipophilicity and higher molecular volume and weight than the antivirals studied, which suggested that these features might not only contribute for new interactions with the HIV-RT but also influence the specificity and consequently the low cytoxicity profile of these compounds. Thus these data point them as promising leading compounds for generating new anti-HIV-RT compounds. [Copyright &y& Elsevier]

Nanotechnology has contributed to the creation of several products and industrial methods. Herein we tested the intercalation of biomaterials into inorganic nanolamellae as pharmaceutical excipients. These materials included sodium and alkylammonium montmorillonite, viscogel B8, ethylcellulose, and chitosan, and the intercalation results success was observed with ethylcellulose and viscogel B8. Thus this nanocomposite was tested with dapsone pills as a model in simulated gastric and enteral fluids and showed a close zero order type kinetics and a higher drug release retardation. This data suggests that this nanocomposite has potential not only for colon specific use but also for prolonged release systems coatings. [ABSTRACT FROM AUTHOR]

Bacterial infections are a significant cause of morbidity and mortality among critically ill patients. The increase of antibiotic resistance in bacteria from human microbiota—such as Staphylococcus epidermidis, an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices—increased the desire for new antibiotics. In this study we designed, synthesized, and determined the antimicrobial activity of 27 thieno[2,3- b]pyridines ( 1, 2, 2a–2m, 3, 3a–3m) derivatives against a drug-resistant clinical S. epidermidis strain. In addition, we performed a structure-activity relationship analysis using a molecular modeling approach, and discuss the drug absorption, distribution, metabolism, excretion, and toxicity profile and Lipinski’s “rule of five,” which are tools to assess the relationship between structures and drug-like properties of active compounds. Our results showed that compound 3b (5-(1H-tetrazol-5-yl)-4-(3`-methylphenylamino)thieno[2,3-b]pyridine) was as active as oxacillin and chloramphenicol but with lower theoretical toxicity risks and a better drug likeness and drug score potential than chloramphenicol. All molecular modeling and biological results reinforced the promising profile of 3b for further experimental investigation and development of new antibacterial drugs. [ABSTRACT FROM AUTHOR]

Abstract: Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a–j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on these molecules, we applied rigid analogue and isosteric replacement approaches to design and synthesize nine new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivatives (2a–i). The biological and computational results of these new molecules were compared with 1-hydroxyacridones. An inhibitory profile was observed in 10-Cl substituted 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivative (2f), which presents the same substituent at the analogous position of 1-hydroxyacridone derivative (1b). The structure–activity relationship (SAR) studies pointed out the 10-position next to nitrogen atom as important for the anti-HSV-1 profile in the pyrazolo-naphthyridine derivatives tested, which reinforced the promising profile for further experimental investigation. The most potent acridone and pyrazolo-naphthridine derivatives were also submitted to an in silico ADMET screening in order to determine their overall drug-score, which confirmed their potential antiviral profile. [Copyright &y& Elsevier]

Abstract: The development of new drugs against Trypanosoma cruzi is still required since the only two drugs currently used cause severe side effects. In this work we described the synthesis, the in vitro biological evaluation, and the SAR results of 1H-pyrazolo[3,4-b]pyridine derivatives, a new antichagasic agent series. The presence of fluorine, hydroxyl or nitro group at Y position resulted in at least one or two promising compounds in each set of derivatives (6f, 6g, 6i, 6l, and 6m). The SAR study showed that trypanocidal activity observed depends on both geometric and stereoelectronic parameters (MEP and frontier molecular orbitals HOMO and LUMO). We also used the Osiris program for calculating and comparing the fragment based druglikeness of the most active derivative (6g) (IC50 =1.9μg/mL), the inactive compound (6o), and the current toxic antichagasic drugs (nifurtimox and benznidazole). Interestingly 6g presented a potential druglikeness higher than nifurtimox and benznidazole while 6o presented the lowest value among them. [Copyright &y& Elsevier]

Abstract: The aim of this work was to describe the synthesis, the in vitro anti-Mycobacterium tuberculosis profile, and the structure–activity relationship (SAR) study of new N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a–l). The reactions of aromatic amine hydrochlorides with diazomalonaldehyde (1) produced several N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a–l) in moderate-to-good yields. In order to investigate the influence of the difluoromethylene group on the anti-Mycobacterium activity of these compounds, fluorination of triazoles with DAST converted the corresponding carbaldehyde compounds into new difluoromethyl derivatives (4a–l) in excellent yield. Characterization of all compounds was achieved by spectroscopic means and additional for 1-(4-methylphenyl)-1,2,3-triazole-4-carbaldehyde, 3k by X-ray crystallography. Compounds (3a–l) and (4a–l) have been screened for the inhibitory activity against Mycobacterium tuberculosis H37Rv strain (ATCC 27294) and all of them were able to inhibit the growth of the bacterium. Interestingly, 3a and 3k exhibited the best inhibition with MIC values of 2.5μg/mL, similar to pharmaceuticals currently used in the treatment of tuberculosis. Our SAR study indicated the importance of the hydrogen bond acceptor subunit (3a–l), the position in the aromatic ring, the planarity of triazole and phenyl rings in these compounds, and a correlation between the uniform HOMO coefficient distribution and the anti-tubercular activity. The significant activity of 3a and 3k pointed them as promising lead molecules for further synthetic and biological exploration. [Copyright &y& Elsevier]

Abstract: Starting from α- and β-lapachones, in this work we compared the biological and theoretical profile of several oxyran derivatives of lapachone as potential trypanocidal agents. Our biological results showed that the oxyrans tested act as trypanocidal agents against Trypanosoma cruzi with minimal cytotoxicity in the VERO cell line compared to naphthoquinones. The oxyran derivative of α-lapachone (7a) showed to be one of the most potent compounds. In our molecular modeling study, we analyzed the C-ring moiety and the redox center of β-lapachone molecule as the moieties responsible for the trypanocidal and cytotoxic effects on mammalian cell line. The computational methods used to delineate the structural requirements for the trypanocidal profile pointed out that the transposition of the C-ring moiety of β-lapachone, combined with its oxyran ring, introduced important molecular requirements for trypanocidal activity in the HOMO energy, HOMO orbital coefficient, LUMO density, electrostatic potential map, dipole moment vector, and calculated log P (clog P) parameter. This study could lead to the development of new antichagasic medicines based on α-lapachone analogs. [Copyright &y& Elsevier]

The chiral GC separation of 2-alkyl-2-keto-γ-butyrolactone derivatives and their alcohol analogs using 2,3-di-O-methyl-6-O-tert.-butyldimethylsilyl-β-cyclodextrin (DIMETBCD) as chiral selector was discussed. The results, supported by the ketone preliminary molecular modelling calculations, suggest that the chiral recognition for DIMETBCD depends more on the geometry than on the polarity of the alkyl substituents on the butyrolactones. Hydrogen bonds and alkyl group steric effects should be an important function of the alcohol chiral recognition for DIMETBCD. Comparison of the retention times of the alcohol derivatives, in achiral and chiral stationary phases, suggests a specific structural effect for the cyclodextrin selector. [Copyright &y& Elsevier]

A series of phthalimide acid derivatives was synthesized and evaluated as leukotriene D4 receptor antagonists. The tetrazolephthalimide LASSBio 552 (7) was shown to be able to inhibit the contractile activity induced by 100 nM of LTD4 in guinea-pig tracheal strips with an IC50=31.2 μM. In addition, LASSBio 552 (7) has been showed to present a better efficacy than zafirlukast (1) used as standard. [Copyright &y& Elsevier]