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Leishmaniasis, an infectious disease caused by pathogenic Leishmania parasites, affects millions of people in developing countries, and its re-emergence in developed countries, particularly in Europe, poses a growing public health concern. The limitations of current treatments and the absence of effective vaccines necessitate the development of novel therapeutics. In this study, we focused on identifying small molecule inhibitors which prevents the interaction between peroxin 5 (PEX5) and peroxisomal targeting signal 1 (PTS1), pivotal for kinetoplastid parasite survival. The Leishmania donovani PEX5, containing a C-terminal tetratricopeptide repeat (TPR) domain, was expressed and purified, followed by the quantification of kinetic parameters of PEX5-PTS1 interactions. A fluorescence polarization-based high-throughput screening assay was developed and small molecules inhibiting the LdPEX5-PTS1 interaction were discovered through the screening of a library of 51,406 compounds. Based on the confirmatory assay, nine compounds showed half maximal inhibitory concentration (IC50) values ranging from 3.89 to 24.50 µM. In silico docking using a homology model of LdPEX5 elucidated that the molecular interactions between LdPEX5 and the inhibitors share amino acids critical for PTS1 binding. Notably, compound P20 showed potent activity against the growth of L. donovani promastigotes, L. major promastigotes, and Trypanosoma brucei blood stream form, with IC50 values of 12.16, 19.21, and 3.06 μM, respectively. The findings underscore the potential of targeting LdPEX5-PTS1 interactions with small molecule inhibitors as a promising strategy for the discovery of new anti-parasitic compounds.

Corporate social responsibility (CSR) and its relationship with corporate competitive advantage (CCA) have gained a tremendous interest among the researchers and practitioners over decades, as evident by the increasing surge of studies in this domain. This study examines how five types (legal, economic, philanthropic, ethical, and environmental) of CSR affect CCA in a developing country through the mediating roles of employee commitment and corporate reputation. Data was collected by survey questionnaires from a sample of 869 participants working at service, real estate, and manufacturing firms in Ho Chi Minh City and Binh Duong Province, Vietnam. SmartPLS 3.0 software and the partial least squares structural equation modeling method (PLS-SEM) were applied to evaluate the research model and test the hypotheses. The findings revealed that different dimensions of CSR have positive significant effects on employee commitment, corporate reputation and competitive advantage. Besides, employee commitment and corporate reputation were found to meditate the relationship between different types of CSR and CCA. These outcomes contributed to the extension of theory in the fields of CSR and offered some suggestions for managers in implementing CSR initiatives to gain and sustain CCA.

A chromone-peptidyl hybrids series was synthesised and rationally repurposed towards identification of potential antileishmanial hits against visceral leishmaniasis. Three hybrids 7c, 7n, and 7h showed potential IC50 values (9.8, 10, and 12 µM, respectively) which were comparable to erufosine IC50 (9.8 µM) but lower potency than miltefosine IC50 (3.5 µM). Preliminary assessment of cytotoxicity using human THP-1 cells presented chromone-peptidyl hybrids 7c and 7n as non-cytotoxic up to 100 µM while erufosine and miltefosine had CC50 of 19.4 µM and >40 µM, respectively. In silico studies pinpointed the N-p-methoxyphenethyl substituent at the peptidyl moiety together with the oxygen-based substituted functions of the phenyl ring of the chromone moiety as crucial players in binding to LdCALP. Together, these findings present chromone-peptidyl hybrids 7c and 7n as potential and anticipated non-cytotoxic antileishmanial hit compounds for possible development of potential antileishmanial agents against visceral leishmaniasis.

The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis (VL), a potentially fatal disease if left untreated. Given the limitations of current therapies, there is an urgent need for new, safe, and effective drugs. To discover novel antileishmanial compounds from previously unexplored chemical spaces, we conducted a high-throughput screening (HTS) of 2562 natural compounds, assessing their activity against L. donovani promastigotes and intracellular amastigotes. Utilizing the criteria of ≥70% parasite growth inhibition and ≥70% host cell (THP-1) viability, we selected 100 inhibitors for half-maximal inhibitory concentration (IC50) value determination. Twenty-six compounds showed activities in both forms of Leishmania with a selectivity index of over 3. Clustering analysis resulted in four chemical clusters with scaffolds of lycorine (cluster 1), 5-hydroxy-9,10-dihydro-4H,8H-pyrano[2,3-f]chromene-4,8-dione (cluster 2), and semi-synthetic derivatives of ansamycin macrolide (cluster 4). The enantiomer of lycorine, BMD-NP-00820, showed the highest anti-amastigote activity with an IC50 value of 1.74 ± 0.27 μM and a selectivity index (SI) > 29. In cluster 3, the most potent compound had an IC50 value of 2.20 ± 0.29 μM with an SI > 23, whereas in cluster 4, with compounds structurally similar to the tuberculosis drug rifapentine, BMD-NP-02085 had an IC50 value of 1.76 ± 0.28 μM, but the SI value was 7.5. Taken together, the natural products identified from this study are a potential source for the discovery of antileishmanial chemotypes for further development.

A series of rosmarinic acid-β-amino-α-ketoamide hybrids were synthesized and rationally repurposed towards the identification of new antileishmanial hit compounds. Two hybrids, 2g and 2h, showed promising activity (IC50 values of 9.5 and 8.8 μM against Leishmania donovani promastigotes, respectively). Their activities were comparable to erufosine. In addition, cytotoxicity evaluation employing human THP-1 cells revealed that the two hybrids 2g and 2h possess no cytotoxic effects up to 100 µM, while erufosine possessed cytotoxicity with CC50 value of 19.4 µM. In silico docking provided insights into structure–activity relationship emphasizing the importance of the aliphatic chain at the α-carbon of the cinnamoyl carbonyl group establishing favorable binding interactions with LdCALP and LARG in both hybrids 2g and 2h. In light of these findings, hybrids 2g and 2h are suggested as potential safe antileishmanial hit compounds for further development of anti-leishmanial agents.

Pervious concrete pavement has been used widely as an effective practice for water management in low-impact development techniques. The hydrologic performance of pervious concrete pavement depends significantly on the rainfall intensity and the designed slope. This study assessed the hydrologic performance of pervious concrete pavement by evaluating the time for surface ponding via finite element analysis. A series of simulations were carried out to explore the relationship between hydrologic performance and pervious concrete pavement by the Hydrus 2D program. The research’s results showed that as the slope increased, the time of surface ponding also increased. The data indicated that the slope variable had a low impact on the water level in pervious concrete pavement under a constant rainfall intensity. Observation of the effect of rainfall intensity showed that when the rainfall intensity increased twofold, the time for surface ponding dropped about two times. Furthermore, when surface ponding appeared, pervious concrete pavement at higher rainfall intensity had lower water content. The rainfall intensity also significantly affects the hydrologic performance of the pervious concrete pavement. This study only assessed the hydrologic performance by using the time for surface ponding via finite element analysis. Further experimental studies should be conducted to examine the relationship of other factors to the hydrologic performance of pervious concrete pavement.

The substitution of traditional copper power transmission cables with lightweight copper–carbon nanotube (Cu–CNT) composite fibers is critical for reducing the weight, fuel consumption, and CO2 emissions of automobiles and aircrafts. Such a replacement will also allow for lowering the transmission power loss in copper cables resulting in a decrease in coal and gas consumption, and ultimately diminishing the carbon footprint. In this work, we created a lightweight Cu–CNT composite fiber through a multistep scalable process, including spinning, densification, functionalization, and double-layer copper deposition. The characterization and testing of the fabricated fiber included surface morphology, electrical conductivity, mechanical strength, crystallinity, and ampacity (current density). The electrical conductivity of the resultant composite fiber was measured to be 0.5 × 106 S/m with an ampacity of 0.18 × 105 A/cm2. The copper-coated CNT fibers were 16 times lighter and 2.7 times stronger than copper wire, as they revealed a gravimetric density of 0.4 g/cm3 and a mechanical strength of 0.68 GPa, suggesting a great potential in future applications as lightweight power transmission cables.

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

Slaughterhouse wastewater (SWW) possesses very high organic and nutrient concentrations and its residues are moderately solubilized, which leads to pollution affecting the environment and human health. The objective of this study was to investigate the effective removal of ammonium in slaughter wastewater by up flow anaerobic sludge blanket (UASB) technology combined with an expanded granular sludge bed (EGSB) using anammox and PVA gel as the biomass carrier. Ammonium loading rates (NLRs) increased from 0.25 kg N-NH4+/m3.d to 0.75 kg N-NH4+/m3.d with hydraulic retention times (HRTs) of 12, 6, and 4 h. The system was operated in 2 phases. In phase 1, the removal of ammonium by employing the combination of UASB technology and EGSB using anammox was examined. The removal efficiencies of nitrite were 52% (NLRs=0.25 kg N-NH4+/m3.d), 69% (NLRs=0.5 kg N-NH4+/m3.d) and 64% (NLRs=0.75 kg N-NH4+/m3.d). On the other hand, the removal efficiencies of ammonium were about 37% (NLRs=0.25 kg N-NH4+/m3.d), 64% (NLRs=0.5 kg N-NH4+/m3.d) and 55% (NLRs=0.75 kg N-NH4+/m3.d). In phase 2, a PVA gel was supplied to the EGSB as the biomass carrier for growing the anammox sludge. The result showed that the removal efficiencies of nitrite were about 55% (NLRs=0.25 kg N-NH4+/m3.d), 77% (NLRs=0.5 kg N-NH4+/m3.d), and 73% (NLRs=0.75 kg N-NH4+/m3.d). In addition, the removal efficiencies of ammonium were about 56% (NLRs=0.25 kg N-NH4+/m3.d), 68% (NLRs=0.5 kg N-NH4+/m3.d), and 60% (NLRs=0.75 kg N-NH4+/m3.d).

Direct growth inhibition of infectious organisms coupled with immunomodulation to counteract the immunosuppressive environment might be a beneficial therapeutic approach. Herein, a library of sulfuretin analogs were developed with potential capabilities to inhibit production of the immunosuppressive PGE2 and elicit direct growth inhibition against Leishmania donovani; the major causative agent of the fatal visceral leishmaniasis. Amongst explored library members bearing diverse methoxy and/or hydroxy substitution patterns at rings B and A, analog 1i retaining the C6-hydroxy moiety at ring-A, but possessing methoxy moieties in place of the polar dihydroxy moieties of sulfuretin ring-B, as well as analog 1q retaining the sulfuretin′s polar dihydroxy moieties at ring-B, but incorporating a C6-methoxy moiety instead of the C6-hydroxy moiety at ring-A, were the most promising hit compounds. Cytotoxicity evaluation suggested that analog 1i possesses a safety profile inducing the death of the parasite rather than host cells. In silico simulation provided insights into their possible binding with Leishmania donovani fumarate reductase. The current investigation presents sulfuretin analogs 1i and 1q as potential hit compounds for further development of multifunctional therapeutic agents against visceral leishmaniasis.

SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including Leishmania and Trypanosoma cruzi spp. However, its in vivo efficacy against protozoa has not been reported. Here, we evaluated the activity of SQ109 in mouse models of Leishmania, Trypanosoma spp. as well as Toxoplasma infection. In the T. cruzi mouse model, 80% of SQ109-treated mice survived at 40 days post-infection. Even though SQ109 did not cure all mice, these results are of interest since they provide a basis for future testing of combination therapies with the azole posaconazole, which acts synergistically with SQ109 in vitro. We also found that SQ109 inhibited the growth of Toxoplasma gondii in vitro with an IC50 of 1.82 µM and there was an 80% survival in mice treated with SQ109, whereas all untreated animals died 10 days post-infection. Results with Trypanosoma brucei and Leishmania donovani infected mice were not promising with only moderate efficacy. Since SQ109 is known to be extensively metabolized in animals, we investigated the activity in vitro of SQ109 metabolites. Among 16 metabolites, six mono-oxygenated forms were found active across the tested protozoan parasites, and there was a ~6× average decrease in activity of the metabolites as compared to SQ109 which is smaller than the ~25× found with mycobacteria.

Kinetoplastid parasites, including Leishmania and Trypanosoma spp., are life threatening pathogens with a worldwide distribution. Next-generation therapeutics for treatment are needed as current treatments have limitations, such as toxicity and drug resistance. In this study, we examined the activities of established mammalian target of rapamycin (mTOR)/phosphoinositide 3-kinase (PI3K) inhibitors against these tropical diseases. High-throughput screening of a library of 1742 bioactive compounds against intracellular L. donovani was performed, and seven mTOR/PI3K inhibitors were identified. Dose-dilution assays revealed that these inhibitors had half maximal effective concentration (EC50) values ranging from 0.14 to 13.44 μM for L. donovani amastigotes and from 0.00005 to 8.16 μM for T. brucei. The results of a visceral leishmaniasis mouse model indicated that treatment with Torin2, dactolisib, or NVP-BGT226 resulted in reductions of 35%, 53%, and 54%, respectively, in the numbers of liver parasites. In an acute T. brucei mouse model using NVP-BGT226 parasite numbers were reduced to under the limits of detection by five consecutive days of treatment. Multiple sequence and structural alignment results indicated high similarities between mTOR and kinetoplastid TORs; the inhibitors are predicted to bind in a similar manner. Taken together, these results indicated that the TOR pathways of parasites have potential for the discovery of novel targets and new potent inhibitors.