Grazing camels under semi-extensive production system: selectivity, feed intake capacity, digestion and energy expenditure.

BACKGROUND: It was proposed that camels are more effective than other livestock species in selecting plants for their nutritional value. They may self-regulate their voluntary feed intake to satisfy their nutritional needs. This study was designed to investigate camels' feeding selectivity and ability to cover nutritional requirements when grazing alfalfa (high in protein) and/ or barley (high in energy) in a desert climate. METHODS: Eighteen lactating camels were equally divided into three feeding treatments. They grazed daily on alfalfa, barley, or a mixed pasture of both, for two periods of one month each. The concentrate supplement was individually administered at 40 g/kg BW0.75, divided into two equal parts, in the morning and in afternoon. Total energy expenditure (EE) was estimated by heart rate (HR) monitors for 48 h after being calibrated by oxygen consumption using an upgraded face mask open-circuit respiratory system. RESULTS: During the first period, camels had a greater forage intake and digestibility when they grazed barley rather than alfalfa, while those grazing mixed pasture performed intermediately. In the second period, camels had a similar forage intake and digestibility among treatments due to a decline in barley intake and digestibility compared to the first period, which was expected since the preferred plant part gradually shifted from barley grains to predominantly straw as a function of time. Similar HR and EE were found across periods and treatments. As a result of greater gross and digestible energy intake in period 1, a better energy balance in period 1 was observed compared to period 2. Camels better utilize barley than alfalfa. Grazing on barley had a higher energy balance than grazing alfalfa alone or in combination with barley. However, camels grazing barley produced lower milk yield and energy than those grazing alfalfa alone or in combination with barley, with no interaction detected between period and treatment. CONCLUSIONS: Lactating camels are able to self-regulate their voluntary intake to cover their energy requirements when they are grazing barley and/or alfalfa supplemented with a concentrate supplement at 40 g/kg BW0.75. Grazing barley is better utilized by camels than alfalfa. The chemical and physical properties of plant species play an important role in the selectivity of foraging camels. It also impacts their intake and digestibility, which is negatively associated with the proportion of cell wall content consumed.

Clinical Significance and Resource Burden of Double Duct Sign in Non-jaundiced Patients.

Aim The study aims to determine the incidence of malignancy at presentation and subsequent risk of malignancy (at 12 months follow-up) in a cohort of patients with double duct sign (DDS) on cross-sectional imaging but no visible stigmata of jaundice. The study also correlates malignancy with liver enzyme dysfunction and estimates the resource burden incurred during the investigation of these patients. Methods A search for the key term "double duct sign" was undertaken in the radiological database of a tertiary hepatopancreatobiliary (HPB) centre between March 2017 and March 2022. Radiological reports, clinic letters, blood results, and multidisciplinary team meeting (MDT) outcomes were reviewed during this period and at one year. The national tariff payment system was reviewed to identify tariffs for different investigations required for the cohort and to calculate the total cost incurred. Results Ninety-seven patients with DDS were identified. Sixty-four patients (66%) had a normal bilirubin (0-21 µmol/L) at presentation and were included in the analysis. Seven patients (10.9%) were diagnosed with malignant peri-ampullary tumours, and 21 (32.8%) were diagnosed with benign diseases. In 34 patients (53%) with DDS, the underlying cause remained uncharacterised. Most patients had mild abnormalities of liver enzymes, but two patients (4.3%) were diagnosed with malignant peri-ampullary tumours despite having normal serological values. Patients who had a benign diagnosis and/or who had cancer excluded without a definitive diagnosis did not go on to develop a malignancy at 12 months follow-up. However, in those patients where the underlying aetiology could not be characterised, extended surveillance was required with a total of 80 MDT discussions and multiple surveillance scans (103 CT and 65 MRI scans). Twenty-six patients underwent endoscopic ultrasound (EUS) with three patients requiring more than one EUS examination (29 investigations in total). The cost of these investigations was £38,926.89. Conclusion This study confirms that DDS even in patients without clinical jaundice or with normal liver enzymes requires careful investigation to exclude malignancy despite the resource burden this entails. This supports previously reported results in the literature, and despite the increased use of cross-sectional imaging, DDS remains a clinically significant finding. Large cohort risk stratification studies would be useful to determine clinical urgency and allow the appropriate allocation of resources.

Effects of the concentration and nature of total dissolved solids in drinking water on feed intake, nutrient digestion, energy balance, methane emission, ruminal fermentation, and blood constituents in different breeds of young goats and hair sheep.

Understanding how different livestock species and breeds respond to consumption of brackish water could improve usage of this resource. Therefore, Angora, Boer, and Spanish goat doelings and Dorper, Katahdin, and St. Croix ewe lambs (6 animals per animal type [AT]; initial age = 296 ± 2.1 days) consuming water with varying concentrations of minerals of a natural brackish water source (BR) and sodium chloride (NaCl; SL) were used to determine effects on water and feed intake, nutrient digestion, heat energy, methane emission, ruminal fluid conditions, and blood constituent concentrations. There were 6 simultaneous 6 (water treatments [WT]) × 6 (AT) Latin squares with 3-wk periods. The WT were fresh (FR), BR alone (100-BR), a similar total dissolved solids (TDS) concentration as 100-BR via NaCl addition to FR (100-SL), BR with concentrations of all minerals increased by approximately 50% (150-BR), a similar TDS level as 150-BR by NaCl addition to FR (150-SL), and a similar 150 TDS level achieved by addition of a 1:1 mixture of BR minerals and NaCl to 100-BR (150-BR/SL). Concentrations (mg/kg) in BR were 4928 TDS, 85.9 bicarbonate, 224.9 calcium, 1175 chloride, 60.5 magnesium, 4.59 potassium, 1387 sodium, 1962 sulfate, and 8.3 boron, and TDS in other WT were 209, 5684, 7508, 8309, and 7319 mg/kg for FR, 100-SL, 150-BR, 150-SL, and 150-BR/SL, respectively. There were very few significant effects of WT or AT × WT interactions, although AT had numerous effects. Water intake was affected by AT (P = 0.02) and WT (P = 0.04), with greater water intake for 150-SL than for FR, 100-BR, 100-SL, and 150-BR. Dry matter intake among AT was lowest (P < 0.05) for Angora. Digestion of organic matter and neutral detergent fiber and heat energy differed among AT (P < 0.05), but nitrogen digestion and ruminal methane emission were similar among AT. Blood aldosterone concentration was higher (P < 0.05) for FR than for other WT. In conclusion, all AT seemed resilient to these WT regardless of mineral source and concentrations, with TDS less than 8300 mg/kg, which did not influence nutrient utilization, ruminal fermentation, energy balance, or blood constituent levels.

The incidence of post cholecystectomy pain (PCP) syndrome at 12 months following laparoscopic cholecystectomy: a prospective evaluation in 200 patients.

OBJECTIVES: Post cholecystectomy pain syndrome can cause significant distress, impairs quality of life and exacerbations often result in emergency visits. Poorly controlled postoperative pain is a recognized cause of persistent postsurgical pain. Abdominal myofascial pain syndrome is an underdiagnosed cause of persistent pain in this cohort. The objective was to estimate the incidence of poorly controlled postoperative pain in the first 48 h after surgery and the likelihood of developing persistent pain at 12 months. METHODS: The patients undergoing laparoscopic cholecystectomy at a tertiary unit were consented for participation in a prospective service evaluation. A telephone review was performed at three, six and twelve months after surgery. Incidence of poorly controlled pain in the first 48 h after surgery was assessed. Patients with persistent pain were referred to the pain clinic. RESULTS: Over a six-month period, 200 patients were assessed. Eleven patients were excluded (5.5 %). Twelve patients were lost to follow-up (6.6 %, 12/189). Patient satisfaction with acute postoperative pain management was low in 40 % (76/189). Poorly controlled postoperative pain was reported by 36 % (68/189) of patients. Incidence of persistent pain was 29 % (54/189) at 12 months post-surgery. Over half of patients with persistent pain (63 %, 34/54) reported poorly controlled postoperative pain. A somatic source was diagnosed in 54 % (29/54) with post cholecystectomy pain syndrome. CONCLUSIONS: Poorly controlled postoperative pain was reported by a third of patients. Persistent pain was present in 29 % at twelve months post-surgery. Abdominal myofascial pain syndrome should be considered as a differential diagnosis in post cholecystectomy pain syndrome.

Composition of the rumen archaeal community of growing camels fed different concentrate levels.

Understanding the rumen fermentation and methanogenic community in camels fed intensively is critical for optimizing rumen fermentation, improving feed efficiency, and lowering methane emissions. Using Illumina MiSeq sequencing, quantitative real-time PCR, and high-performance liquid chromatography, this study evaluates the influence of different concentrate supplement levels in the diet on rumen fermentation as well as the diversity and structure of the rumen methanogenic community for growing dromedary camels. Twelve growing camels were divided into three groups and given three levels of concentrate supplement, 0.7% (C1), 1% (C2), and 1.3% (C3) based on their body weight. All animals were fed alfalfa hay ad libitum. The levels of total volatile fatty acid, rumen ammonia, and methanogen copy number were unaffected by the supplementation level. Increasing the concentrate supplement level increased the proportion of propionic acid while decreasing the proportion of acetic acid. Increasing the level of concentrate in the diet had no effect on alpha diversity metrics or beta diversity of rumen methanogens. Methanobrevibacter and Methanosphaera predominated the methanogenic community and were declined as concentrate supplement level increased. This study sheds new light on the effect of concentrate supplement level in growing camels' diet on rumen fermentation and methanogenic community, which could help in the development of a strategy that aimed to reduce methane emissions and enhance feed efficiency.

Discriminant Analysis of the Prognostic Factors for Hearing Outcomes in Patients with Idiopathic Sudden Sensorineural Hearing Loss.

BACKGROUND: This study aims to determine and assess prognostic variables that might affect the hearing result in patients with idiopathic sudden sensorineural hearing loss following intratympanic steroid injection. METHODS: In total, 190 patients with idiopathic sudden sensorineural hearing loss received intratympanic steroid injection. Two hearing indices (recovery and nonrecovery) will be analyzed as dependent variables; patient's age, time period between the onset of hearing loss and treatment, initial level of hearing (hearing loss pre), type of audiogram curve (upsloping, downsloping, and flat), presence of vertigo, presence of tinnitus, and diabetes) will be analyzed as prognostic factor variables. RESULTS: Recovery was seen in 72% of the patients. Different preinjection audiogram curves and hearing grades had a significant effect on recovery, absence of vestibular symptoms and no diabetic history were noted to have a good prognosis. Delay in treatment by more than 30 days from the onset of hearing loss was associated with a worse prognosis. CONCLUSION: Idiopathic sudden sensorineural hearing loss associated with late treatment plan more than 1 month, presence of vertigo, diabetes, and profound prehearing loss were negative prognostic factors. Whereas age, gender, and presence of tinnitus did not affect prognosis. More stable response was obtained when intratympanic steroids were added within 1 month after diagnosis, and the patient presented with mild or moderate hearing loss grade, flat or downsloping pure tone audiometery curve, and absence of vertigo and nondiabetic with significantly good results.

Antimicrobial, anticancer and immunomodulatory potential of new quinazolines bearing benzenesulfonamide moiety.

Sulfonamides are privileged candidates with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and could replenish the MRSA antibiotic pipeline. The initial screening of a series of quinazolinone benzenesulfonamide derivatives 5-18 against multidrug-resistant bacterial and fungal strains revealed their potent activity. The promising compounds were conjugated with ZnONPs to study the effect of nanoparticle formation on the antimicrobial, cytotoxic and immunomodulatory activity. Compounds 5, 11, 16 and 18 revealed promising antimicrobial and cytotoxic activities with superior safety profiles and enhanced activity upon nanoformulation. The immunomodulatory potential of compounds 5, 11, 16 and 18 was assessed. Compounds 5 and 11 demonstrated an increase in spleen and thymus weight and boosted the activation of CD4+ and CD8+ T lymphocytes, confirming their promising antimicrobial, cytotoxic and immunomodulatory activity.

Effect of concentrates level on digestibility, ruminal fermentation, and bacterial community in growing camels.

Understanding the rumen microbiota of camels under different feeding conditions is necessary to optimize rumen fermentation and productivity. This study aims to investigate the effects of different concentrate supplement levels on digestion, rumen fermentation and bacteria in growing camels. Fifteen growing camels were divided into three groups and were fed alfalfa hay in addition to one of the three concentrate supplement levels based on body weight (BW): low (0.7%), medium (1%), and high (1.3%). Increasing the concentrate supplement level in the diet increased total dry matter intake but had no effect on nutrients digestibility, except for crude protein digestibility, which was enhanced with the high concentrate level. Growing camels at low-level had considerably higher rumen pH than those fed medium or high levels. Increasing the supplement level also increased rumen propionic acid but decreased acetic acid concentration. Principal coordinate analysis showed that concentrate levels clearly separated the ruminal bacterial communities where Bacteroidetes and Firmicutes were the dominant phyla and Prevotella, Ruminococcus, Butyrivibrio, RC9_gut_group, and Fibrobacteres were the dominant bacterial genera. This study expands our knowledge regarding the rumen microbiota of growing camels under different concentrate levels and reveals that medium concentrate levels could be appropriate for growing camels.

Biogenic synthesis of CuO-NPs as nanotherapeutics approaches to overcome multidrug-resistant Staphylococcus aureus (MDRSA).

Due to the misuse of antibiotics, the multidrug-resistant Staphylococcus aureus (MDRSA) has caused serious infections and become more difficult to deal with. Here we propose to synthesise copper oxide nanoparticles (CuO-NPs) using a cell-free filter of Streptomyces rochei to enhance antibiotics activity against (MDRSA) and kill them. Characterisation of CuO-NPs using ultraviolet, dynamic light scattering, zeta potential, transmission electron microscopic (TEM), and X-ray diffraction, were investigated. The antibacterial action of the CuO-NPs was tested against standard strain and clinical isolates using the agar well diffusion method and the microdilution assay. The results showed the monodispersed spherical shape CuO-NPs with a mean diameter of 10.7 nm and were found to be active against (MDRSA). By a combination of CuO-NPs with different antibiotics, the highest synergistic effect was observed with cefoxitin, the minimum inhibitory concentration (MIC) was reduced to 6.5 for CuO-NPs, and 19.5 for cefoxitin. Time-kill assay showed the highest reduction in log10 colony-forming unit (CFU)/ml of initial inoculum of MRSA after 24 h. The HFB-4 cells cultured in the presence of CuO-NPs showed normal morphology with 100% viability at 8 µg/ml. TEM showed that combination (1/4 MIC cefoxitin +1/16 MIC CuO-NPs) highly damages bacterial cells' shape. The biosynthesis CuO-NPs showed antibacterial activity against S. aureus suggesting a promising alternative in clinical.

Solar radiation-induced synthesis of bacterial cellulose/silver nanoparticles (BC/AgNPs) composite using BC as reducing and capping agent.

In the present work, a simple, novel, and ecofriendly method for synthesis of silver nanoparticles (AgNPs) and BC/AgNP composite using bacterial cellulose (BC) nanofibers soaked in AgNO3 solution under induction action of solar radiation. The photochemical reduction of silver Ag + ions into silver nanoparticles (Ago) was confirmed using UV visible spectra; the surface plasmon resonance of synthesized AgNPs was localized around 425 nm. The mean diameter of AgNPs obtained by DLS analysis was 52.0 nm with a zeta potential value of - 9.98 mV. TEM images showed a spherical shape of AgNPs. The formation of BC/AgNP composite was confirmed by FESEM, EDX, FTIR, and XRD analysis. FESEM images for BC showed the 3D structures of BC nanofibers and the deposited AgNPs in the BC crystalline nanofibers. XRD measurements revealed the high crystallinity of BC and BC/AgNP composite with crystal sizes of 5.13 and 5.6 nm, respectively. BC/AgNP composite and AgNPs exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria. The present work introduces a facile green approach for BC/AgNP composite synthesis and its utility as potential food packaging and wound dressings, as well as sunlight indicator application.

Bacillus megaterium-Mediated Synthesis of Selenium Nanoparticles and Their Antifungal Activity against Rhizoctonia solani in Faba Bean Plants.

Rhizoctonia root-rot disease causes severe economic losses in a wide range of crops, including Vicia faba worldwide. Currently, biosynthesized nanoparticles have become super-growth promoters as well as antifungal agents. In this study, biosynthesized selenium nanoparticles (Se-NPs) have been examined as growth promoters as well as antifungal agents against Rhizoctonia solani RCMB 031001 in vitro and in vivo. Se-NPs were synthesized biologically by Bacillus megaterium ATCC 55000 and characterized by using UV-Vis spectroscopy, XRD, dynamic light scattering (DLS), and transmission electron microscopy (TEM) imaging. TEM and DLS images showed that Se-NPs are mono-dispersed spheres with a mean diameter of 41.2 nm. Se-NPs improved healthy Vicia faba cv. Giza 716 seed germination, morphological, metabolic indicators, and yield. Furthermore, Se-NPs exhibited influential antifungal activity against R. solani in vitro as well as in vivo. Results revealed that minimum inhibition and minimum fungicidal concentrations of Se-NPs were 0.0625 and 1 mM, respectively. Moreover, Se-NPs were able to decrease the pre-and post-emergence of R. solani damping-off and minimize the severity of root rot disease. The most effective treatment method is found when soaking and spraying were used with each other followed by spraying and then soaking individually. Likewise, Se-NPs improve morphological and metabolic indicators and yield significantly compared with infected control. In conclusion, biosynthesized Se-NPs by B. megaterium ATCC 55000 are a promising and effective agent against R. solani damping-off and root rot diseases in Vicia faba as well as plant growth inducer.

High rate of bleeding and arterial thrombosis in COVID-19: Saudi multicenter study.

BACKGROUND: Several observational studies have reported the rate of venous and arterial thrombotic events in patients infected with COVID-19, with conflicting results. The aim of this study was to estimate the rate of thrombotic and bleeding events in hospitalized patients diagnosed with Coronavirus disease 2019 (COVID-19). METHODS: This was a multicenter study of 636 patients admitted between 20 March 2020 and 31 May 2020 with confirmed COVID-19 in four hospitals. RESULTS: Over a median length of stay in the non-ICU group of 7 days and of 19 days in the ICU group, twelve patients were diagnosed with Venous thromboembolism (VTE) (1.8 %) (95 % CI, 1.1-3). The rate in the non-ICU group was 0.19 % (95 % CI, 0.04-0.84), and that in the ICU group was 10.3 % (95 % CI, 6.4-16.2). The overall rate of arterial event is 2.2 % (95 % CI, 1.4-3.3). The rates in the non-ICU and ICU groups were 0.94 % (95 % CI, 0.46-0.1.9) and 8.4 % (95 % CI, 5.0-14.0). The overall composite event rate was 2.9 % (95 % CI, 2.0-4.3). The composite event rates in the non-ICU and ICU groups were 0.94 % (95 % CI, 0.46-0.1.9) and 13.2 % (95 % CI, 8.7-19.5). The overall rate of bleeding is 1.7 % (95 % CI, 1.0-2.8). The bleeding rate in the non-ICU group was 0.19 % (95 % CI, 0.04-0.84), and that in the ICU group was 9.4 % (95 % CI, 5.7-15.1). The baseline D-dimer level was a significant risk factor for developing VTE (OR 1.31, 95 % CI, 1.08-1.57, p = 0.005) and composite events (OR 1.32, 95 % CI, 1.12-1.55, p = 0.0007). CONCLUSIONS: In this study, we found that the VTE rates in hospitalized patients with COVID-19 might not be higher than expected. In contrast to the risk of VTE, we found a high rate of arterial and bleeding complications in patients admitted to the ICU. An elevated D-dimer level at baseline could predict thrombotic complications in COVID-19 patients and may assist in the identification of these patients. Given the high rate of bleeding, the current study suggests that the intensification of anticoagulation therapy in COVID-19 patients beyond the standard of care be pursued with caution and would best be evaluated in a randomized controlled study.

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors.

Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a-d, pyridine-2-one 3-10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17-23.87 µM, and of DHFR, with IC50 values of 4.33-5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.

Design, synthesis, antimicrobial activity and molecular docking studies of some novel di-substituted sulfonylquinoxaline derivatives.

2,3-Dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride 1 was prepared via reaction of o-phenylene diamine with oxalic acid followed by chlorosulfonation with excess chlorosulfonic acid. A series of new sulfonylquinoxaline derivatives 2-6 were obtained upon reacting compound 1 with different types of amines. 2,3-Dichloro-6-morpholinosulfonylquinoxaline derivative 6 was subjected to further chemical reactions to afford many derivatives of 6-morpholino 2,3-disubstitutedquinoxalines, thus reaction of compound 6 with different secondary amines yielded mono and di secondary aminoquinoxaline derivatives 7-10 depending on the reactivity difference of the two chlorine atoms. Hydrazinolysis of compound 7 furnished hydrazino quinoxaline derivatives 11a-c. Additionally triazolo and pyrazolyl quinoxaline derivatives 12-14 were obtained through the reaction of compound 11a with phenyl isothiocyanate, formylpyrazole and ethyl acetoacetate. All the synthesized compounds were screened for their antibacterial and antifungal activities. Compounds 7a, 9b, 10a, 10c, 10f and 11c showed good to moderate antimicrobial activity against the tested Gram-positive, Gram-negative bacteria and fungi with MIC values ranging from 2.44 to 180.14 µM. Their MBC values were also evaluated using the same tested microorganisms. Moreover, screening against multi-drug resistant strains revealed the promiscuity of these new derivatives, especially compound 7a that showed comparable antibacterial activity (MIC 4.91-9.82 µM) with Norfloxacin (MIC 2.44-9.80 µM). Furthermore, these compounds were evaluated as DNA Gyrase inhibitors and the obtained results were in the range of 15.69-23.72 µM. Immunomodulatory effect was also investigated and compounds 7a, 11c, 10f, 10c, 10a and 9b showed high immunostimulatory action with ratio (142.6 ± 0.4, 135.7 ± 0.5, 117.8 ± 0. 39, 112.5 ± 0. 83, 86.4 ± 0. 47, 72.8 ± 0. 77) respectively. Molecular docking studies of the promising derivatives into DNA Gyrase binding site proved the usefulness of hybridizing quinoxaline scaffold with SO2 and morpholine moieties as a hopeful strategy in designing new DNA Gyrase binding molecules.

Improving the Functional Activities of Curcumin Using Milk Proteins as Nanocarriers.

Curcumin is one of the most common spices worldwide. It has potential benefits, but its poor solubility and bioavailability have restricted its application. To overcome these problems, this study aimed to assess the efficacy of sodium caseinate (SC), α-lactalbumin (α-La), ß-lactoglobulin (ß-lg), whey protein concentrate (WPC) and whey protein isolate (WPI) as nanocarriers of curcumin. Furthermore, the antioxidant, anticancer and antimicrobial activities of the formed nanoparticles were examined. The physicochemical characteristics of the formed nanoparticles as well as the entrapment efficiency (%) and the in vitro behavior regarding the release of curcumin (%) were examined. The results showed that the formation of curcumin-milk protein nanoparticles enhanced both the entrapment efficiency and the in vitro behavior release of curcumin (%). Cur/ß-lg nanoparticles had the highest antioxidant activity, while SC and WPC nanoparticles had the highest anticancer effect. The antimicrobial activity of the formed nanoparticles was much higher compared to curcumin and the native milk proteins.

Discovery of New Schiff Bases Tethered Pyrazole Moiety: Design, Synthesis, Biological Evaluation, and Molecular Docking Study as Dual Targeting DHFR/DNA Gyrase Inhibitors with Immunomodulatory Activity.

A series of Bis-pyrazole Schiff bases (6a-d and 7a-d) and mono-pyrazole Schiff bases (8a-d and 9a-d) were designed and synthesized through the reaction of 5-aminopyrazoles 1a-d with aldehydes 2-5 using mild reaction condition with a good yield percentage. The chemical structure of newly formed Schiff bases tethered pyrazole core was confirmed based on spectral and experimental data. All the newly formed pyrazole Schiff bases were evaluated against eight pathogens (Gram-positive, Gram-negative, and fungi). The result exhibited that, most of them have good and broad activities. Among those, only six Schiff bases (6b, 7b, 7c, 8a, 8d, and 9b) displayed MIC values (0.97-62.5 µg/mL) compared to Tetracycline (15.62-62.5 µg/mL) and Amphotericin B (15.62-31.25 µg/mL), MBC values (1.94-87.5 µg/mL) and selectivity to tumor cell than normal cells. Immunomodulatory activities showed that the promising Schiff bases increase the immunomodulator effect of defense cell and the Schiff base 8a is the highest one by (Intra. killing activity = 136.5 ± 0.3%) having a pyrazole moiety as well as amide function (O=C-NH2) and piperidinyl core. Furthermore, the most potent one exhibited broad activity depending on both MIC and MBC values. Moreover, to study the mechanism of these pyrazole Schiff bases, two active Schiff bases 8a and 9b from six derivatives were introduced to study the enzyme assay as dihydrofolate reductase (DHFR) on E. coli organism and DNA gyrase with two different organisms, S. aureus and B. subtilis, to determine the inhibitory activities with lower values in the case of DNA gyrase (8a and 9b) or nearly as DHFR compound 9b, while pyrazole 8a showed excellent inhibitory against all enzyme assay. The molecular docking study against dihydrofolate reductase and DNA gyrase were performed to study the binding between active site in the pocket with the two Schiff bases (8a and 9b) that exhibited good binding affinity with different bond types as H-bonding, aren-aren, and arene-cation interaction as well as study the physicochemical and pharmacokinetic properties of the two active Schiff bases 8a and 9b.

Novel N-(Substituted) Thioacetamide Quinazolinone Benzenesulfonamides as Antimicrobial Agents.

AIM: With the rapid emergence of antibiotic resistance, efforts are being made to obtain new selective antimicrobial agents. Hybridization between quinazolinone and benzenesulfonamide can provide new antimicrobial candidates. Also, the use of nanoparticles can help boost drug efficacy and lower side effects. MATERIALS AND METHODS: Novel quinazolinone-benzenesulfonamide derivatives 5-18 were synthesized and screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, MRSA and yeast. The most potent compound 16 was conjugated with copper oxide nanoparticles 16-CuONPs by gamma irradiation (4.5 KGy). Characterization was performed using UV-Visible, TEM examination, XRD patterns and DLS. Moreover, compound 16 was used to synthesize two nanoformulations: 16-CNPs by loading 16 in chitosan nanoparticles and the nanocomposites 16-CuONPs-CNPs. Characterization of these nanoformulations was performed using TEM and zeta potential. Besides, the inhibitory profile against Staphylococcus aureus DNA gyrase was assayed. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs on normal VERO cell line was carried out to determine its relative safety. Molecular docking of 16 was performed inside the active site of S. aureus DNA gyrase. RESULTS: Compound 16 was the most active in this series against all the tested strains and showed inhibition zones and MICs in the ranges of 25-36 mm and 0.31-5.0 µg/mL, respectively. The antimicrobial screening of the synthesized nanoformulations revealed that 16-CuONPs-CNPs displayed the most potent activity. The MBCs of 16 and the nanoformulations were measured and proved their bactericidal mode of action. The inhibitory profile against S. aureus DNA gyrase showed IC50 ranging from 10.57 to 27.32 µM. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs against normal VERO cell lines proved its relative safety (IC50= 927, 543 and 637 µg/mL, respectively). Molecular docking of 16 inside the active site of S. aureus DNA gyrase showed that it binds in the same manner as that of the co-crystallized ligand, ciprofloxacin. CONCLUSION: Compound 16 could be considered as a new antimicrobial lead candidate with enhanced activity upon nanoformulation.

Antimicrobial evaluation of thiadiazino and thiazolo quinoxaline hybrids as potential DNA gyrase inhibitors; design, synthesis, characterization and morphological studies.

A series of thiadiazino[5,6-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives was designed and synthetized from the reaction of 2,3-dichloro-6-(morpholinosulfonyl)quinoxaline (2) with thiosemicarbazide or thiocarbohydrazide and thiourea derivatives to give nineteen quinoxaline derivatives 3-16. All the synthesized compounds were evaluated for in vitro antimicrobial potential against various bacteria and fungi strains that showed considerable antimicrobial activity against tested microorganisms. The most potent compounds 2, 7, 9, 10, 12 and 13c were exhibited bactericidal activity, in addition to fungistatic activity by dead live assay. Moreover, these compounds showed a significant result against all multi-drug resistance (MDRB) used especially compound 13c that displayed the best results with MICs of MDRB (1.95, 3.9, 2.6, 3.9 µg/mL) for stains used in this study, compared with Norfloxacin (1.25, 0.78, 1.57, 3.13 µg/mL). Also, cytotoxicity on normal cell (Vero cells ATCC CCL-81) by MTT assay was performed with lower toxicity results. Additionally, morphological studies, immunostimulatory potency and DNA gyrase inhibition assay of most active compounds was done. A molecular docking study has also been carried out to support the effective binding of the most promising compounds at the active site of the target enzyme S. aureus DNA gyrase (2XCT).

Biological Evaluation and Molecular Docking with In Silico Physicochemical, Pharmacokinetic and Toxicity Prediction of Pyrazolo[1,5-a]pyrimidines.

Pyrazolo[1,5-a]pyrimidines 5a-c, 9a-c and 13a-i were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory activity. The biological activities of pyrazolo[1,5-a]pyrimidines showed that the pyrazolo[1,5-a]pyrimidines (5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h) displayed promising antimicrobial and immunomodulatory activities. Studying the in silico predicted physicochemical, pharmacokinetic, ADMET and drug-likeness properties for the pyrazolo[1,5-a]pyrimidines 5a-c, 9a-c and 13a-i confirmed that most of the compounds (i) were within the range set by Lipinski's rule of five, (ii) show higher gastrointestinal absorption and inhibition of some CYP isoforms, and (iii) have a carcinogenicity test that was predicted as negative and hERG test that presented medium risk. Moreover, the molecular docking study demonstrated that the compounds 5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h are potent inhibitors of 14-alpha demethylase, transpeptidase and alkaline phosphatase enzymes. This study could be valuable in the discovery of a new series of drugs.

Design, synthesis, in vitro antimicrobial evaluation and molecular docking studies of indol-2-one tagged with morpholinosulfonyl moiety as DNA gyrase inhibitors.

A series of Schiff bases 3, 5, 7 and hydrazones 9 were achieved via reaction of 5-(morpholinosulfonyl)indol-2,3-dione (1) with appropriate amines and/or hydrazide derivatives. Representative compounds of the synthesized products were tested and evaluated as antimicrobial agents. According to MIC and MBC results from compounds 9a, 9c, 7a, 3b, 3c, and 5b were able to exhibit significant antibacterial activity against both Gram-positive and Gram-negative bacteria together with moderate antifungal activities. Also, a multi-drug resistance study (MDRS) was carried out to evaluate the activity of most potent compounds, and these compounds showed considerable results compared with Norfloxacin and Tetracycline which observed no results against strains used in this study. The inhibitory activity of most potent compounds (3b, 3c, 5b, 7a, 9a, and 9c) against DNA gyrase isolated from S. aureus was examined. The results indicated that all of these derivatives inhibiting DNA gyrase and therefore lead to separate bacterial DNA and inhibit cell division. Compounds 3b, 9c showed to be very potent inhibitors towards S. aureus DNA gyrase with IC50 values (18.75 ± 1.2 and 19.32 ± 0.99 µM) respectively, compared with Ciprofloxacin (26.43 ± 0.64 µM). Molecular docking studies indicated that the synthesized compounds observed good binding with the enzyme and showed lower binding energy of the most promising compounds than a standard drug used, and enabled a better understanding of their structural features.