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Background: Coronavirus disease-19 (COVID-19) is a newly emerged pandemic leading to a state of international alert and leaving millions of infections and thousands of deaths all over the world. Analysis of statistics and epidemiological data for the pandemic outcome pinpointed a puzzling influence of human sex on the heterogeneous outcome of COVID-19, where hospital admissions and mortality were higher among males than females. Two theories explained the observed male-biased COVID-19 mortality based on either dosage of immunoregulatory genes coded in X- chromosomes, or on the abundance of the angiotensin-converting enzyme two (ACE2) receptors in males than females. Objective: In our study, we propose a third scenario through virtual screening of direct antiviral effects of sex hormones. Materials and Methods: Updated screening statistics from 47 countries displaying sex-disaggregated data on COVID-19 were employed and visualized in the form of heatmaps depicting sex difference effects on statistics of cases and deaths. Molecular docking and binding simulations of investigated sex steroids against COVID-19 specific proteins were investigated. Results: Analysis of COVID-19 sex-disaggregated data confirmed that male-biased mortality and computer-aided docking found unexpected female sex hormones biased binding against key targets implicated in the life cycle of COVID-19 compared to the male sex hormone testosterone. Other investigated steroids showed promising docking scores, while the male sex hormone exhibited the lowest affinity. Conclusion: Female sex hormones virtually exhibit direct anti-COVID-19 effect, the proposed antiviral effect of sex hormones should be considered to explain the outcomes of mortality. Moreover, the fluctuation of sex hormones influences sex and personal derived-differential response to COVID-19 infection.

Klebsiella pneumoniae is an opportunistic pathogen causing nosocomial and community-acquired infections. Klebsiella has developed resistance against antimicrobials including the last resort class; carbapenem. Currently, treatment options for carbapenem-resistant-Klebsiella (CRK) are very limited. This study aims to restore carbapenem effectiveness against CRK using celastrol and thymol. Clinical Klebsiella isolates were identified using biochemical and molecular methods. Antimicrobial susceptibility was determined using disk-diffusion method. Carbapenemase-production was tested phenotypically and genotypically. Celastrol and thymol-MICs were determined and the carbapenemase-inhibitory effect of sub-MICs was investigated. Among 85 clinical Klebsiella isolates, 72 were multi-drug-resistant and 43 were meropenem-resistant. Phenotypically, 39 isolates were carbapenemase-producer. Genotypically, blaNDM1 was detected in 35 isolates, blaVIM in 17 isolates, blaOXA in 18 isolates, and blaKPC was detected only in 6 isolates. Celastrol showed significant inhibitory effect against carbapenemase-hydrolytic activity. Meropenem-MIC did not decrease in presence of celastrol, only 2-fold decrease was observed with thymol, while 4–64 fold decrease was observed when meropenem was combined with both celastrol and thymol. Furthermore, thymol increased CRK cell wall-permeability. Molecular docking revealed that celastrol is superior to thymol for binding to KPC and VIM-carbapenemase. Our study showed that celastrol is a promising inhibitor of multiple carbapenemases. While meropenem-MIC were not affected by celastrol alone and decreased by only 2-folds with thymol, it decreased by 4–64 folds in presence of both celastrol and thymol. Thymol increases the permeability of CRK-envelope to celastrol. The triple combination (meropenem/celastrol/thymol) could be useful for developing more safe and effective analogues to restore the activity of meropenem and other β-lactams.

Antimicrobial agents are essential to protect human and animal health. During the coronavirus disease 2019 pandemic, antimicrobials such as cephalosporins were widely used as prophylactics and to prevent bacterial co-infection. Undoubtedly, the prevalence of antibiotics in the aquatic environment will ultimately affect the degree of resistance against these bacteria in animals and the environmental systems. In order to monitor 16 cephalosporins in the aquatic environment, we developed a new liquid chromatography-tandem mass spectrometry method that functioned simultaneously under positive and negative electrospray ionization switching modes. The chromatographic separation has been implemented using a pentafluorophenyl propyl column kept at 40°C. The limits of detection and quantitation for the studied cephalosporins ranged from (8 × 10

Background: Schistosoma mansoni infection is associated with hepatic fibrosis and portal hypertension. Previous studies reported that blocking some components of rennin angiotensin system can ameliorate the liver pathology induced by S. mansoni infection. Aim: The present study investigated the potential effect of losartan, an angiotensin II receptor antagonist, and enalapril, an angiotensin-converting enzyme inhibitor, on hepatic fibrosis caused by S. mansoni in a murine model. Materials and Methods: S. mansoni-infected mice were treated at week 5 after infection with losartan, enalapril, or their combination. A group of infected mice was treated with the reference drug praziquantel (PZQ) as controls. Parasitological and histological parameters were investigated. Results: Our results showed that when compared with enalapril, treatment with losartan alone caused a considerable decrease in liver index (28.92% versus 25.09%), spleen index (47.19% versus 37.08%), worm burden (38.7% versus 24.8%), hepatic tissue egg load (62.7% versus 54%), granuloma size (40.4% versus 29.4%) and fibrosis (48.7% versus 29.4%). The combination of losartan and enalapril did not produce a more pronounced effect than those of losartan. Conclusion: Our results suggest the promising effect of enalapril and losartan in amelioration of hepatic pathology but further studies to determine their effects in combination with other antischistosomal agents such as praziquantel are recommended.

Background: Literature survey has pointed out that Benzimidazoles represent an interesting class of anthelmintics, of which several potent members were developed. Objective: Benzimidazoles hybridized with pharmacophoric moieties possessing anthelmintic activity were designed, synthesized to be evaluated against cercaria. Methods: Structural modification was achieved through 2- and 5-positions. Moreover, an in vitro cercarial assay was adopted to evaluate target compounds. Results and Discussion: Biological screening revealed that compound 3h showed significant activity with a survival index of 35% at a 100 μg/mL concentration. Whereas, compounds 3a and 3c showed moderate activity, the rest of the tested compounds exhibited low activity. Conclusion: The current study evidenced that the new hybrids "benzimidazole-thiophen-aryl" are successful as cercacidal agents. Further studies of this novel tri-ring system are suggested on adult worms of S. mansoni.

Quinolines have a weighty effect as anticancer agents and 1,4-DHPs have demonstrated efficacy as anticancer agents in several studies, as well. New hybrid models of symmetric and asymmetric 1,4-DHPs and pyridines linked at C

Background: Quinoline scaffold acts as “privileged structure” for anticancer drug design. Certain derivatives showed good results through different mechanisms as topoisomerase 1 and kinase inhibition. Methods: A new series of 2-chloro-3-(2-amino-3-cyano-4H-chromene, 4H-pyranyl and fused 1- cyclohexen-4-yl)quinoline structures (3-5, 6 and 7) were designed, synthesized, and evaluated for their in vitro antitumor activity. All compounds were tested by MTT assay against a panel of four different human tumor cell lines. The inhibitory activity of selected compounds was assessed on topoisomerase 1 and epidermal growth factor receptor tyrosine kinase via ELISA. In addition, compounds 7b and 3a were docked into the X-ray crystal structure of Topo 1 and EGFR enzymes, respectively to explain the molecular basis of the potent activity. Results: Compounds 3a, 3b and 7b showed characteristic efficacy profile. 7b showed the best cytotoxic activity on all types of tested cell lines with IC50 range (15.8±1.30 to 28.2±3.37 µM), relative to 5-fluoruracil of IC50 range (40.7±2.46 to 63.8±2.69 µM). Via ELISA, 7b and 3a showed characteristic inhibition profile on Topo 1 and EGFR-TK respectively. In addition, 7b has scored binding energy (101.61 kcal/mol) and six hydrogen bonds with amino acids conserved residues in the enzyme pocket. Conclusion: Analysis of results revealed that compounds 7a and 7b mainly were Topo 1 inhibitors while 3a was mainly EGFR inhibitor. This property may be exploited to design future quinoline derivatives as antitumor agents with enhanced selectivity towards either of the two molecular targets.

Soil hosts myriads of living organisms with the extensive potential to produce bioactive compounds. Bacteria are the major soil inhabitants that represent a rich reservoir for antibiotic production along with their role in recycling nutrients and maintenance of the soil ecosystem. Here, from 55 tested soil samples, we isolated and identified a novel antibiotic-producing bacterial strain with a phylogenetically closest match to Bacillus subtilis sp. based on BLASTN search of GenBank for the 16S rRNA gene sequence. We characterized this novel strain through microscopic, biochemical, and molecular techniques, combined with testing its potential antimicrobial activity. Chemical studies revealed that the antibiotic produced by this strain is a glycopeptide. It exhibited profound activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans. The antibiotic is optimally produced at 37 °C after 28 h of growth. The biocompatibility of the extracted antibiotic was tested over a wide range of factors including temperature, pH, surfactants, and metal salts. To confirm its therapeutic potential, a sterile solution of the antibiotic was tested in vivo against bacteria-induced keratitis in rats where significant healing activity was recorded. Hence, this soil Bacillus strain may lead to the development of novel antibiotics for the treatment of human pathogens.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of nosocomial infections because of its high resistance. Here, we study the antibiotic resistance in MRSA clinical isolates and their relation to integron I occurrence. A total of 88 clinical Staphylococcusaureus isolates were collected. MRSA were identified by the disk diffusion method (DDM) and confirmed by PCR, and antibiogram was determined by DDM. Integron I, II and the aacA4 gene were investigated by PCR. Integrase-positive strains were analyzed for the presence of resistance gene cassettes by sequencing. All isolates were identified as MRSA by DDM and confirmed by PCR. All isolates were resistant to ampicillin and cefoxitin. Concerning aminoglycosides, the frequency of resistance was reported for streptomycin (60.7%), tobramycin (37.1%) gentamicin (36%), and for amikacin (15.9%). Integron I was detected in 41 isolates (46.6%), while integron II was detected in three isolates (3.4%). Sequencing of the integron I-cassette indicated the exclusive prevalence of addA gene variants mediating aminoglycoside resistance. The aacA4 gene was found in DNA of 31 isolates (35.22%). This study revealed the high existence of MRSA. Furthermore, the AacA4 gene and class I integron harboring aadA gene were predominant in MRSA isolates.

Schistosomiasis is one of the neglected diseases causing considerable morbidity and mortality throughout the world. Microtubules with its main component, tubulin play a vital role in helminthes including schistosomes. Benzimidazoles represent potential drug candidates by binding β-tubulin. The study aimed to generate a homology model for the β-tubulin of S. mansoni using the crystal structure of O vis aries (Sheep) β-tubulin (PDB ID: 3N2G D) as a template, then different β-tubulin models were generated and two previously reported benzimidazole derivatives (NBTP-F and NBTP-OH) were docked to the generated models, the binding results indicated that both S. mansoni, S. haematobium were susceptible to the two NBTP derivatives. Additionally, three mutated versions of S. mansoni β-tubulin wild-type were generated and the mutation (F185Y) seems to slightly enhance the ligand binding. Dynamics simulation experiments showed S. haematobium β-tubulin is highly susceptible to the tested compounds; similar to S. mansoni, moreover, mutated models of S. mansoni β-tubulin altered its NBTPs susceptibility. Moreover, additional seven new benzimidazole derivatives were synthesized and tested by molecular docking on the generated model binding site of S. mansoni β-tubulin and were found to have good interaction inside the pocket.

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/) Candida albicans is the causative agent of fatal systemic candidiasis. Due to limitations of antifungals, new drugs are needed. The anti-virulence effect of plant essential oils (EOs) was evaluated against clinical C. albicans isolates including cinnamon, clove, jasmine and rosemary oils. Biofilm, phospholipase and hemolysin were assessed phenotypically. EOs were evaluated for their anti-virulence activity using phenotypic methods as well as scanning electron microscopy (SEM) and atomic force microscopy (AFM). Among the C. albicans isolates, biofilm, phospholipase and hemolysins were detected in 40.4, 86.5 and 78.8% of isolates, respectively. Jasmine oil showed the highest anti-biofilm activity followed by cinnamon, clove and rosemary oils. SEM and AFM analysis showed reduced adherence and roughness in the presence of EOs. For phospholipase, rosemary oil was the most inhibitory, followed by jasmine, cinnamon and clove oils, and for hemolysins, cinnamon had the highest inhibition followed by jasmine, rosemary and clove oils. A molecular docking study revealed major EO constituents as promising inhibitors of the Als3 adhesive protein, with the highest binding for eugenol, followed by 1,8-cineole, 2-phenylthiolane and cinnamaldehyde. In conclusion, EOs have a promising inhibitory impact on Candida biofilm, phospholipase and hemolysin production, hence EOs could be used as potential antifungals that impact virulence factors. Faculty yes

Schistosomiasis represents a public health problem and praziquantel is the only drug used for treatment of all forms of the disease. Thus, the development of new anti-schistosomal agents is of utmost importance to increase the effectiveness, reduce side effects and delay the emergence of resistance. The present study was conducted to report the therapeutic efficacy of PPQ-8, a new synthetic quinoline-based compound against Schistosoma mansoni. Mice were treated with PPQ-8 at day 49 post infection using two treatment regimens (20 and 40 mg/kg). Significant reductions were recorded in hepatic (62.9% and 83.6%) and intestinal tissue egg load (57.4% and 73.5%), granuloma count (75.4% and 89.1%) and diameter (26.2% and 47.3%), in response to the drug regimens, respectively. In addition, both treatment regimens induced significant decrease in liver (23.3% and 32.8%) and spleen (37.5% and 45.3%) indices. Also, there were significant reductions in mature ova, total worm and female count, which were more prominent with the higher dose. The reduction in the level of nitric oxide in the liver by both therapeutic regimens to 22.5% and 47.2% indicates the anti-oxidant activity of PPQ-8. Bright field microscopic examination of worms recovered from infected and PPQ-8-treated mice showed nearly empty intestinal caeca with no observable changes in the tegument. Our findings hold promise for the development of a novel anti-schistosomal drug using PPQ-8, but further in vitro and in vivo studies are needed to elucidate the possible mechanism/s of action and to study the effect of PPQ-8 on other human schistosomes.

Schistosomiasis is still a public health problem. Praziquantel is the only drug available for treatment of all forms of human schistosomiasis. Although praziquantel is an effective drug against all species of human schistosomes, concerns about resistance have been raised, especially in endemic areas. A hybrid compound containing several pharmacophore within a single molecule is a promising strategy. Here, we described the anti-schistosomal effect of 4-(2-Chloroquinolin-3-yl)-2-oxo-6-(p-tolyl)-1,2-dihydropyridine-3-carbonitrile (PPQ-6), a hybrid drug based on quinoline and pyridine. PPQ-6 was given as two regimens (20 or 40 mg/kg). In both regimens, PPQ-6 significantly reduced liver and spleen indices, nitric oxide production, tissue egg load, hepatic granuloma size and count, immature eggs and total worm burden especially females. Our findings suggested that PPQ-6 is a promising anti-schistosomal agent; however more research is needed to elucidate its mechanism of action and report its activity on juvenile schistosomes and other species of human schistosomes.

2-Amino-4-(2-chloroquinolin-3-yl)-7-hydroxy-4H-chromene-3-carbonitrile (3a) is a quinoline derivative that has been shown to possess antitumor activity. Beside activity, the compound has reasonable solubility in aqueous buffers. Herein, we tested its activity as potential ligand for s-Catenin protein as molecular target. We used Water-LOGSY NMR as our method of choice to test the binding. A selective binding of 3a to s-Catenin was observed, suggesting that the high antitumor potency of 3a may result, in part, from its ability to bind s-Catenin; in addition to other known quinoline mechanisms. This property may be exploited to design future quinoline therapeutic strategies targeting s-Catenin related diseases such as colorectal cancer.

Objective: To test the effect of benzimidazole-derived compound (compound BTP-Iso) on cultured adult Schistosoma mansoni and clean Biomphalaria alexandrina snails. Methods: Adult schistosomes were incubated at different concentrations of compound BTP-Iso to calculate mortality rate, LC90 and LC50, in addition, tegumental changes were recorded using SEM. Clean Biomphalaria alexandrina snails were also incubated with compound BTP-Iso at various concentrations to report snail mortality. Results: Compound BTP-Iso was found to possess potent antischistosomal activities on adult worms but no effect was recorded on snail host. At a concentration of 8 µg/mL, mortality rates were 45.8% and 81.0% after 48 h and 72 h incubation, respectively, while 100% mortality was recorded after 48 h incubation at 20.0 µg/mL and after 72 h incubation at 10.0 µg/mL, with LC50 and LC 90 of 6.1 µg/mL and 9.8 µg/mL, respectively. Morphological changes and tegumental alternation of treated worms suggested loss of the tegument and its vital functions. Conclusions: This study provided the evidence for the potential antischistosomal effect of compound BTP-Iso and its possible uses as an alternative chemotherapeutic agent for treatment of schistosomiasis.

Objective: To evaluate the in vitro antischistosomal activity of two new synthetic benzimidazole-related compounds: NBTP-OH and NBTP-F. Methods: Schistosoma adult worms were recovered from mice infected with Schistosoma mansoni cercaria, washed and then incubated in the culture media with different concentrations of compounds NBTP-OH and NBTP-F up to 72 h. Scanning electron microscopy was conducted to report morphological changes. Results: Incubation of adult Schistosoma mansoni with 10 μg/mL of NBTP-OH for 48 h killed 81.25% of worms. The calculated LC50 and LC90 72 h post-incubation were 6.8 μg/mL and 9.8 μg/ mL, respectively. Exposure of worms to 10 μg/mL of NBTP-F killed 89.5% of worms after 48 h, mostly males (83.3%), the LC50 and LC90 after 72 h of incubation were 4.8 μg/mL and 6.9 μg/mL, respectively. Worms incubated for 72 h with these compounds revealed swelling and deformity of oral sucker, disorganization and erosion of the tegument when examined with scanning electron microscopy. Conclusions: NBTP-OH and NBTP-F possess in vitro antischistosomal activities; however, in vivo studies should be conducted to examine their antischistosomal effects.

Toxoplasma gondii is a widely distributed protozoan parasite, which affects worm-blooded animals including human. The commonest chemotherapeutics used for treatment of symptomatic toxoplasmosis have numerous adverse effects. Thus there is an eminent need to develop new therapeutic agents. Here we described the therapeutic efficacy of 4-(2-chloroquinolin-3-yl)-6-(2,5-dimethoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (PPQ-8); a quinoline-related compound in a mouse model of acute and chronic toxoplasmosis. In acute infection, PPQ-8 decreased the parasite load in liver and spleen with amelioration of the hepatic and splenic pathology. In addition, recovered tachyzoites showed distorted shapes, reduced sizes, irregularities, surface protrusions, erosions and peeling besides apical region distortion when seen by scanning electron microscopy. In chronic toxoplasmosis, PPQ-8 produced degeneration and reduction of the brain cysts without stimulating a damaging inflammatory response within the brain. In both models acute and chronic, PPQ-8 prolonged the survival time of mice. These findings hold promise for the development of a novel anti-toxoplasmosis drug using PPQ-8, but further in vivo studies should be carried out to elucidate PPQ-8 mechanism of action and to report its efficacy in combination with other anti-toxoplasmosis agents.

Currently, praziquantel is the only drug of choice for treatment of schistosomiasis. Reports of praziquantel resistance raise concerns about future control of the disease. Therefore, the search for new schistosomicidal drugs is eminent. In this study, the effect of a novel benzimidazole-derived compound (compound BTP-Iso) was assessed in mice harboring adult Schistosoma mansoni (Egyptian strain). Mice were treated 42 days p.i. with compound BTP-Iso using two treatment regimens (200 or 300 mg/kg). In both regimens, there were significant reductions in the number of recovered S. mansoni worms especially females and in immature ova, in addition to a significant reduction in the number and size of hepatic granulomata. A dose of 300 mg/kg resulted in a significant decrease in intestinal and hepatic tissue egg loads. Effect on schistosomes was confirmed by scanning electron microscopy, where adult worms recovered from mice treated with 200 mg/kg of compound BTP-Iso revealed tegumental alternations, characterised by swelling of tegumental ridges, bleb formation, and mild erosion in male worms; however in females, there were extensive erosion and destruction of the tegumental surface. These promising results may encourage future use of compound BTP-Iso in the treatment of schistosomiasis. However, more research is needed to detect the effect of compound BTP-Iso on early developmental stages of S. mansoni and on other species of human schistosomes.