Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer.

Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CaV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.

Identification of 3-Aryl-1-benzotriazole-1-yl-acrylonitrile as a Microtubule-Targeting Agent (MTA) in Solid Tumors.

Recently, a compound derived from recent scientific advances named 34 has emerged as the focus of this research, the aim of which is to explore its potential impact on solid tumor cell lines. Using a combination of bioinformatics and biological assays, this study conducted an in-depth investigation of the effects of 34. The results of this study have substantial implications for cancer research and treatment. 34 has shown remarkable efficacy in inhibiting the growth of several cancer cell lines, including those representing prostate carcinoma (PC3) and cervical carcinoma (HeLa). The high sensitivity of these cells, indicated by low IC50 values, underscores its potential as a promising chemotherapeutic agent. In addition, 34 has revealed the ability to induce cell cycle arrest, particularly in the G2/M phase, a phenomenon with critical implications for tumor initiation and growth. By interfering with DNA replication in cancer cells, 34 has shown the capacity to trigger cell death, offering a new avenue for cancer treatment. In addition, computational analyses have identified key genes affected by 34 treatment, suggesting potential therapeutic targets. These genes are involved in critical biological processes, including cell cycle regulation, DNA replication and microtubule dynamics, all of which are central to cancer development and progression. In conclusion, this study highlights the different mechanisms of 34 that inhibit cancer cell growth and alter the cell cycle. These promising results suggest the potential for more effective and less toxic anticancer therapies. Further in vivo validation and exploration of combination therapies are critical to improve cancer treatment outcomes.

Design, Synthesis, and Antiviral Activities of New Benzotriazole-Based Derivatives.

Several human diseases are caused by enteroviruses and are currently clinically untreatable, pushing the research to identify new antivirals. A notable number of benzo[d][1,2,3]triazol-1(2)-yl derivatives were designed, synthesized, and in vitro evaluated for cytotoxicity and antiviral activity against a wide spectrum of RNA positive- and negative-sense viruses. Five of them (11b, 18e, 41a, 43a, 99b) emerged for their selective antiviral activity against Coxsackievirus B5, a human enteroviruses member among the Picornaviridae family. The EC50 values ranged between 6 and 18.5 µM. Among all derivatives, compounds 18e and 43a were interestingly active against CVB5 and were selected to better define the safety profile on cell monolayers by transepithelial resistance test (TEER). Results indicated compound 18e as the hit compound to investigate the potential mechanism of action by apoptosis assay, virucidal activity test, and the time of addition assay. CVB5 is known to be cytotoxic by inducing apoptosis in infected cells; in this study, compound 18e was proved to protect cells from viral infection. Notably, cells were mostly protected when pre-treated with derivative 18e, which had, however, no virucidal activity. From the performed biological assays, compound 18e turned out to be non-cytotoxic as well as cell protective against CVB5 infection, with a mechanism of action ascribable to an interaction on the early phase of infection, by hijacking the viral attachment process.

Improving in vivo oral bioavailability of a poorly soluble drug: a case study on polymeric versus lipid nanoparticles.

Poorly soluble drugs must be appropriately formulated for clinical use to increase the solubility, dissolution rate, and permeation across the intestinal epithelium. Polymeric and lipid nanocarriers have been successfully investigated for this aim, and their physicochemical properties, and in particular, the surface chemistry, significantly affect the pharmacokinetics of the drugs after oral administration. In the present study, PLGA nanoparticles (SS13NP) and solid lipid nanoparticles (SS13SLN) loaded with SS13, a BCS IV model drug, were prepared. SS13 bioavailability following the oral administration of SS13 (free drug), SS13NP, or SS13SLN was compared. SS13NP had a suitable size for oral administration (less than 300 nm), a spherical shape and negative zeta potential, similarly to SS13SLN. On the contrary, SS13NP showed higher physical stability but lower encapsulation efficiency (54.31 ± 6.66%) than SS13SLN (100.00 ± 3.11%). When orally administered (0.6 mg of drug), SS13NP showed higher drug AUC values with respect to SS13SLN (227 ± 14 versus 147 ± 8 µg/mL min), with higher Cmax (2.47 ± 0.14 µg/mL versus 1.30 ± 0.15 µg/mL) reached in a shorter time (20 min versus 60 min). Both formulations induced, therefore, the oral bioavailability of SS13 (12.67 ± 1.43% and 4.38 ± 0.39% for SS13NP and SS12SLN, respectively) differently from the free drug. These in vivo results confirm that the chemical composition of nanoparticles significantly affects the in vivo fate of a BCS IV drug. Moreover, PLGA nanoparticles appear more efficient and rapid than SLN in allowing drug absorption and transport to systemic circulation.

Antibiotics and Carbohydrate-Containing Drugs Targeting Bacterial Cell Envelopes: An Overview.

Certain bacteria constitute a threat to humans due to their ability to escape host defenses as they easily develop drug resistance. Bacteria are classified into gram-positive and gram-negative according to the composition of the cell membrane structure. Gram-negative bacteria have an additional outer membrane (OM) that is not present in their gram-positive counterpart; the latter instead hold a thicker peptidoglycan (PG) layer. This review covers the main structural and functional properties of cell wall polysaccharides (CWPs) and PG. Drugs targeting CWPs are discussed, both noncarbohydrate-related (ß-lactams, fosfomycin, and lipopeptides) and carbohydrate-related (glycopeptides and lipoglycopeptides). Bacterial resistance to these drugs continues to evolve, which calls for novel antibacterial approaches to be developed. The use of carbohydrate-based vaccines as a valid strategy to prevent bacterial infections is also addressed.

Design, synthesis, and biological screening of a series of 4'-fluoro-benzotriazole-acrylonitrile derivatives as microtubule-destabilising agents (MDAs).

Introduction: Colchicine-binding site inhibitors are some of the most interesting ligands belonging to the wider family of microtubule-destabilising agents.Results: A novel series of 4'-fluoro-substituted ligands (5-13) was synthesised. The antiproliferative activity assays resulted in nM values for the new benzotriazole-acrylonitrile derivatives. Compound 5, the hit compound, showed an evident blockade of HeLa cell cycle in the G2-M phase, but also a pro-apoptotic potential, and an increase of early and late apoptotic cells in HeLa and MCF-7 cell cycle analysis. Confocal microscopy analysis showed a segmented shape and a collapse of the cytoskeleton, as well as a consistent cell shrinkage after administration of 5 at 100 nM. Derivative 5 was also proved to compete with colchicine at colchicine-binding site, lowering its activity against tubulin polymerisation. In addition, co-administration of 5 and doxorubicin in drug-resistant A375 melanoma cell line highlighted a synergic potential in terms of inhibition of cell viability.Discussion: The 4'-fluoro substitution of benzotriazole-acrylonitrile scaffold brought us a step forward in the optimisation process to obtain compound 5 as promising MDA antiproliferative agent at nanomolar concentration.

Benzimidazole-2-Phenyl-Carboxamides as Dual-Target Inhibitors of BVDV Entry and Replication.

Bovine viral diarrhea virus (BVDV), also known as Pestivirus A, causes severe infection mostly in cattle, but also in pigs, sheep and goats, causing huge economical losses on agricultural farms every year. The infections are actually controlled by isolation of persistently infected animals and vaccination, but no antivirals are currently available to control the spread of BVDV on farms. BVDV binds the host cell using envelope protein E2, which has only recently been targeted in the research of a potent and efficient antiviral. In contrast, RdRp has been successfully inhibited by several classes of compounds in the last few decades. As a part of an enduring antiviral research agenda, we designed a new series of derivatives that emerged from an isosteric substitution of the main scaffold in previously reported anti-BVDV compounds. Here, the new compounds were characterized and tested, where several turned out to be potent and selectively active against BVDV. The mechanism of action was thoroughly studied using a time-of-drug-addition assay and the results were validated using docking simulations.

Long-Lasting Efficacy of Radio Electric Asymmetric Conveyer Neuromodulation Treatment on Functional Dysmetria, an Adaptive Motor Behavior.

Background Fluctuating asymmetry (FA) is widely defined as the deviation from perfect bilateral symmetry and is considered an epigenetic measure of environmental stress. Rinaldi and Fontani hypothesized that the FA morpho-functional changes originate from an adaptive motor behavior determined by functional alterations in the cerebellum and neural circuits, not caused by a lesion, but induced by environmental stress. They called this phenomenon functional dysmetria (FD). On this premise, they developed the radio electric asymmetric conveyer (REAC) technology, a neuromodulation technology aimed at optimizing the best neuro-psycho-motor strategies in relation to environmental interaction. Aims Previous studies showed that specific REAC neuro postural optimization (NPO) treatment can induce stable FD recovery. This study aimed to verify the duration of the NPO effect in inducing the stable FD recovery over time. Materials and methods Data were retrospectively collected from a population of 29,794 subjects who underwent a specific semiological FD assessment and received the NPO treatment, regardless of the pathology referred. Results The analysis of the data collected by the various participants in the study led us to ascertain the disappearance of FD in 100% of the cases treated, with a stability of the result detected up to 18 years after the single administration of the REAC NPO treatment. Conclusions The REAC NPO neurobiological modulation treatment consisting of a single administration surprisingly maintains a very long efficacy in the correction of FD. This effect can be explained as the long-lasting capacity of the NPO treatment to induce greater functional efficiency of the brain dynamics as proven in previous studies.

Quinoxaline-based efflux pump inhibitors restore drug susceptibility in drug-resistant nontuberculous mycobacteria.

Nontuberculous mycobacteria (NTM) comprise several ubiquitous, environmentally localized bacteria that may be responsible for serious human diseases. NTM-associated pulmonary infections largely affect individuals with underlying respiratory disease or chronic disease and immunosuppressed patients. Mycobacterium simiae and M. abscessus are two NTMs responsible for lung disease in immunocompetent and immunocompromised individuals. In this study, two NTM strains were isolated from two patients admitted to an Italian hospital and were identified as M. simiae and M. abscessus. The two NTMs were tested for drug susceptibility against different antibiotics. To restore drug susceptibility, a new series of 2-aryl-3-phenoxymethyl-quinoxaline derivatives (QXs) was designed, synthesized, and investigated as efflux pump inhibitors (EPIs) against two clinical isolates of the above-cited NTMs, evaluating how EPIs can influence the drug minimal inhibitory concentration values and, therefore, the activity. The different\ resistance levels tracked in the clinical strains were reduced by EPIs, and in several cases, the susceptibility was completely restored. QXs also resulted as potential chemical probes to be used in drug susceptibility tests to identify the resistance origin when detected.

Is Class-Incremental Enough for Continual Learning?

The ability of a model to learn continually can be empirically assessed in different continual learning scenarios. Each scenario defines the constraints and the opportunities of the learning environment. Here, we challenge the current trend in the continual learning literature to experiment mainly on class-incremental scenarios, where classes present in one experience are never revisited. We posit that an excessive focus on this setting may be limiting for future research on continual learning, since class-incremental scenarios artificially exacerbate catastrophic forgetting, at the expense of other important objectives like forward transfer and computational efficiency. In many real-world environments, in fact, repetition of previously encountered concepts occurs naturally and contributes to softening the disruption of previous knowledge. We advocate for a more in-depth study of alternative continual learning scenarios, in which repetition is integrated by design in the stream of incoming information. Starting from already existing proposals, we describe the advantages such class-incremental with repetition scenarios could offer for a more comprehensive assessment of continual learning models.

Human Enterovirus B: Selective Inhibition by Quinoxaline Derivatives and Bioinformatic RNA-Motif Identification as New Targets.

The Enterovirus genus includes many viruses that are pathogenic in humans, including Coxsackie viruses and rhinoviruses, as well as the emerging enteroviruses D68 and A71. Currently, effective antiviral agents are not available for the treatment or prevention of enterovirus infections, which remain an important threat to public health. We recently identified a series of quinoxaline derivatives that were provento be potent inhibitors of coxsackievirus B5, the most common and a very important human pathogen belonging to the enterovirus genus. We have shown how most active derivatives interfere with the earliest stages of viral replication, blocking infection. Considering the broad antiviral spectrum, a very attractive property for an antiviral drug, we aimed to investigate the antiviral activity of the most promising compounds against other Enterovirus species. Here, we investigated the susceptibility of a panel of representatives of Enterovirus genus (enterovirus A71, belonging to A species; coxsackieviruses B4 and B3;echovirus 9, belonging to B species; and enterovirus D68, belonging to D species) to quinoxaline inhibitors. We also tested cytotoxicity and selectivity indices of the selected compounds, as well as their effects on virus yield.We also investigated their potential mechanism of action by a time course assay. In addition, a bioinformatic analysis was carried out to discover potential new conserved motifs in CVB3 and CVB4 compared to the other enterovirus species that can be used as new targets.

A Lead-Based Fragment Library Screening of the Glycosyltransferase WaaG from Escherichia coli.

Glucosyl transferase I (WaaG) in E. coli catalyzes the transfer of an α-d-glucosyl group to the inner core of the lipopolysaccharide (LPS) and plays an important role in the biogenesis of the outer membrane. If its activity could be inhibited, the integrity of the outer membrane would be compromised and the bacterium would be susceptible to antibiotics that are normally prevented from entering the cell. Herein, three libraries of molecules (A, B and C) were docked in the binding pocket of WaaG, utilizing the docking binding affinity as a filter to select fragment-based compounds for further investigations. From the results of the docking procedure, a selection of compounds was investigated by molecular dynamics (MD) simulations to obtain binding free energy (BFE) and KD values for ligands as an evaluation for the binding to WaaG. Derivatives of 1,3-thiazoles (A7 and A4) from library A and 1,3,4-thiadiazole (B33) from library B displayed a promising profile of BFE, with KD < mM, viz., 0.11, 0.62 and 0.04 mM, respectively. Further root-mean-square-deviation (RMSD), electrostatic/van der Waals contribution to the binding and H-bond interactions displayed a favorable profile for ligands A4 and B33. Mannose and/or heptose-containing disaccharides C1-C4, representing sub-structures of the inner core of the LPS, were also investigated by MD simulations, and compound C42- showed a calculated KD = 0.4 µM. In the presence of UDP-Glc2-, the best-docked pose of disaccharide C42- is proximate to the glucose-binding site of WaaG. A study of the variation in angle and distance was performed on the different portions of WaaG (N-, the C- domains and the hinge region). The Spearman correlation coefficient between the two variables was close to unity, where both variables increase in the same way, suggesting a conformational rearrangement of the protein during the MD simulation, revealing molecular motions of the enzyme that may be part of the catalytic cycle. Selected compounds were also analyzed by Saturation Transfer Difference (STD) NMR experiments. STD effects were notable for the 1,3-thiazole derivatives A4, A8 and A15 with the apo form of the protein as well as in the presence of UDP for A4.

Catastrophic Forgetting in Deep Graph Networks: A Graph Classification Benchmark.

In this work, we study the phenomenon of catastrophic forgetting in the graph representation learning scenario. The primary objective of the analysis is to understand whether classical continual learning techniques for flat and sequential data have a tangible impact on performances when applied to graph data. To do so, we experiment with a structure-agnostic model and a deep graph network in a robust and controlled environment on three different datasets. The benchmark is complemented by an investigation on the effect of structure-preserving regularization techniques on catastrophic forgetting. We find that replay is the most effective strategy in so far, which also benefits the most from the use of regularization. Our findings suggest interesting future research at the intersection of the continual and graph representation learning fields. Finally, we provide researchers with a flexible software framework to reproduce our results and carry out further experiments.

Biological Effects on µ-Receptors Affinity and Selectivity of Arylpropenyl Chain Structural Modification on Diazatricyclodecane Derivatives.

Opioid analgesics are clinically used to relieve severe pain in acute postoperative and cancer pain, and also in the long term in chronic pain. The analgesic action is mediated by µ-, δ-, and κ-receptors, but currently, with few exceptions for k-agonists, µ-agonists are the only ones used in therapy. Previously synthesized compounds with diazotricyclodecane cores (DTDs) have shown their effectiveness in binding opioid receptors. Fourteen novel diazatricyclodecanes belonging to the 9-propionyl-10-substituted-9,10-diazatricyclo[4.2.1.12,5]decane (compounds 20-23, 53, 57 and 59) and 2-propionyl-7-substituted-2,7-diazatricyclo[4.4.0.03,8]decane (compounds 24-27, 54, 58 and 60) series, respectively, have been synthesized and their ability to bind to the opioid µ-, δ- and κ-receptors was evaluated. Five of these derivatives, compounds 20, 21, 24, 26 and 53, showed µ-affinity in the nanomolar range with a negligible affinity towards δ- and κ-receptors and high µ-receptor selectivity. The synthesized compounds showed µ-receptor selectivity higher than those of previously reported methylarylcinnamyl analogs.

Continual learning for recurrent neural networks: An empirical evaluation.

Learning continuously during all model lifetime is fundamental to deploy machine learning solutions robust to drifts in the data distribution. Advances in Continual Learning (CL) with recurrent neural networks could pave the way to a large number of applications where incoming data is non stationary, like natural language processing and robotics. However, the existing body of work on the topic is still fragmented, with approaches which are application-specific and whose assessment is based on heterogeneous learning protocols and datasets. In this paper, we organize the literature on CL for sequential data processing by providing a categorization of the contributions and a review of the benchmarks. We propose two new benchmarks for CL with sequential data based on existing datasets, whose characteristics resemble real-world applications. We also provide a broad empirical evaluation of CL and Recurrent Neural Networks in class-incremental scenario, by testing their ability to mitigate forgetting with a number of different strategies which are not specific to sequential data processing. Our results highlight the key role played by the sequence length and the importance of a clear specification of the CL scenario.

A comprehensive assessment of a new series of 5',6'-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs).

Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E) (Z)-2-(5,6-difluoro-(1H)2H-benzo[d] [1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1-10 µM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 µM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, ß-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine-9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules.

Synthesis, Antitumor and Antiviral In Vitro Activities of New Benzotriazole-Dicarboxamide Derivatives.

Cancer and viral infections continue to threaten humankind causing death worldwide. Hence, the discovery of new anticancer and antiviral agents still represents a major scientific goal. Heterocycles designed to mimic the chemical structure of natural pyrimidines and purines have been designed over the years, exerting their activity acting as false substrates on several different targets. We reported a series of bis-benzotriazole-dicarboxamide derivatives which inhibit viral helicase of poliovirus, and hence we planned structure modifications to obtain different series of new dicarboxamides. Here, the synthesis and characterization of 56 new compounds: 31 bis-benzotriazole dicarboxamides and 25 mono-substituted acidic derivatives are reported. The synthesized compounds were tested for their antiviral and antitumor activity. Mostly, compounds 4a, 4c and 4d showed antiviral activity against tested Picornaviruses, Coxsackievirus B5 and Poliovirus-1. Likewise, four derivatives (3b, 3d, 4d, 9b) showed notable antiproliferative activity inhibiting cell growth in two distinct antitumor screenings. Compound 3b was selected as the antitumor lead compound for the wide range of activity and the potency proved. The lead compound was proved to induce apoptosis in SK-MES1 tumor cells, in a dose-dependent manner.

Inhibition of Enterovirus A71 by a Novel 2-Phenyl-Benzimidazole Derivative.

Enterovirus A71 (EV-A71) infection has emerged as a significant public health concern atthe global level. Epidemic events of EV-A71 have been reported worldwide, and this succession of outbreaks has heightened concern that EV-A71 may become a public health threat. In recent years, widespread A71 enterovirus also occurred in European countries. EV-A71 infection causes hand-foot-mouth disease (HFMD), herpangina, and fever. However, it can sometimes induce a variety of neurological complications, including encephalitis, aseptic meningitis, pulmonary edema, and acute flaccid paralysis. We identified new benzimidazole derivatives and described their in vitro cytotoxicity and broad-spectrum anti-enterovirus activity. Among them, derivative 2b resulted in interesting activity against EV-A71, and therefore it was selected for further investigations. Compound 2b proved to be able to protect cell monolayers from EV-A71-induced cytopathogenicity, with an EC50 of 3 µM. Moreover, Vero-76 cells resulted in being significantly protected from necrosis and apoptosis when treated with 2b at 20 and 80 µM. Compound 2b reduced viral adsorption to Vero-76 cells, and when evaluated in a time-of-addition assay, the derivative had the highest effect when added during the infection period. Moreover, derivative 2b reduced viral penetration into host cells. Besides, 2b did not affect intestinal monolayers permeability, showing no toxic effects. A detailed insight into the efficacy of compound 2b against EV-A71 showed a dose-dependent reduction in the viral titer, also at low concentrations. Mechanism of action investigations suggested that our derivative can inhibit viral endocytosis by reducing viral attachment to and penetration into host cells. Pharmacokinetic and toxicity predictions validated compound 2b as a good candidate for further in vivo assays.

Antiviral effect of Hornstedtia bella Skornick essential oil from the whole plant against vaccinia virus (VV).

In the prevention of epidemic and pandemic emerging and neglected viral infections, natural products are an important source of lead compounds. Hornstedtia bella Skornickis is a rhizomatous herb growing in the forest of central Vietnam. Hornstedtia bella essential oil (Hb EO) was recently characterised by our group as endowed of antimicrobial activity against Staphylococcus aureus Methicillin-Resistant strains. Here, we describe for the first time the evaluation of Hb EO against a spectrum of viruses responsible for important human diseases. Hb EO resulted active against Vaccinia virus (VV) (EC50 values 80 µg/mL), closely related to variola virus, causative agent of smallpox. Hb EO was able to strongly reduce the viral VV titer in cell-based assay at not cytotoxic concentration and its potential mode of action was characterised by virucidal activity evaluation followed by time-of-addition assay. Furthermore, Hb EO antiviral activity was implemented in a combination study with the mycophenolic acid.

Solid Lipid Nanoparticles as Formulative Strategy to Increase Oral Permeation of a Molecule Active in Multidrug-Resistant Tuberculosis Management.

The role of mycobacterial efflux pumps in drug-resistant tuberculosis has been widely reported. Recently, a new compound, named SS13, has been synthesized, and its activity as a potential efflux inhibitor has been demonstrated. In this work, the chemical-physical properties of the SS13 were investigated; furthermore, a formulative study aimed to develop a formulation suitable for oral administration was performed. SS13 shows nonintrinsic antitubercular activity, but it increases the antitubercular activity of all the tested drugs on several strains. SS13 is insoluble in different simulated gastrointestinal media; thus, its oral absorption could be limited. Solid lipid nanoparticles (SLNs) were, therefore, developed by using two different lipids, Witepsol and/or Gelucire. Nanoparticles, having a particle size (range of 200-450 nm with regards to the formulation composition) suitable for intestinal absorption, are able to load SS13 and to improve its permeation through the intestinal mucosa compared to the pure compound. The cytotoxicity is influenced by the concentration of nanoparticles administered. These promising results support the potential application of these nanocarriers for increasing the oral permeation of SS13 in multidrug-resistant tuberculosis management.