Synthesis, in vitro antiurease, in vivo antinematodal activity of quinoline analogs and their in-silico study.

Synthesis of quinoline analogs and their urease inhibitory activities with reference to the standard drug, thiourea (IC50 = 21.86 ± 0.40 µM) are presented in this study. The inhibitory activity range is (IC50 = 0.60 ± 0.01 to 24.10 ± 0.70 µM) which displayed that it is most potent class of urease inhibitor. Analog 1-9, and 11-13 emerged with many times greater antiurease potential than thiourea, in which analog 1, 2, 3, 4, 8, 9, and 11 (IC50 = 3.50 ± 0.10, 7.20 ± 0.20, 1.30 ± 0.10, 2.30 ± 0.10, 0.60 ± 0.01, 1.05 ± 0.10 and 2.60 ± 0.10 µM respectively) were appeared the most potent ones among the series. In this context, most potent analogs such as 1, 3, 4, 8, and 9 were further subjected for their in vitro antinematodal study against C. elegans to examine its cytotoxicity under positive control of standard drug, Levamisole. Consequently, the cytotoxicity profile displayed that analogs 3, 8, and 9 were found with minimum cytotoxic outline at higher concentration (500 µg/mL). All analogs were characterized through 1H NMR, 13C NMR and HR-EIMS. The protein-ligand binding interaction for most potent analogs was confirmed via molecular docking study.

Synthesis, α-glycosidase inhibitory potential and molecular docking study of benzimidazole derivatives.

A series of twenty-six analogs of benzimidazole based oxadiazole have been synthesized and evaluated against alpha-glycosidase enzyme. Most the analogs showed excellent to good inhibitory potential. Among the screened analogs, analog 1, 2, 3 and 14 with IC50 values 4.6 ± 0.1, 9.50 ± 0.3, 2.6 ± 0.1 and 9.30 ± 0.4 µM respectively showedexcellent inhibitory potential than reference drug acarbose (IC50 = 38.45 ± 0.80 µM). Some of the analogs like 19, 21, 22 and 23 with methyl and methoxy substituent on phenyl ring show hydrophobic interaction and were found with no inhibitory potential. The binding interactions between synthesized analogs and ligands protein were confirmed through molecular docking study. Various spectroscopic techniques like 1H NMR, 13C NMR, and EI-MS were used for characterization of all synthesized analogs. These derivatives were synthesized by simple mode of synthesis like heterocyclic ring formation.

Synthesis of Chromen-4-One-Oxadiazole Substituted Analogs as Potent ß-Glucuronidase Inhibitors.

Chromen-4-one substituted oxadiazole analogs 1-19 have been synthesized, characterized and evaluated for ß-glucuronidase inhibition. All analogs exhibited a variable degree of ß-glucuronidase inhibitory activity with IC50 values ranging in between 0.8 ± 0.1-42.3 ± 0.8 µM when compared with the standard d-saccharic acid 1,4 lactone (IC50 = 48.1 ± 1.2 µM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.

Synthesis, Molecular Docking and ß-Glucuronidase Inhibitory Potential of Indole Base Oxadiazole Derivatives.

ß-glucuronidase is a lysosomal glycosidase enzyme which catalyzes the extracellular matrix of cancer and normal cells and the glycosaminoglycans of the cell membrane, which is important for cancer cell proliferation, invasion, and metastasis. Liver cancer, colon carcinoma, and neoplasm bladder are triggered by the increase of the level of ß-glucuronidase activity. The most valuable structures are indole and oxadiazole which has gain immense attention because of its pharmacological behavior and display many biological properties. Twenty-two (1⁻22) analogs of indole based oxadiazole were synthesized and screened for their inhibitory potential against ß-glucuronidase. Majority of the compounds showed potent inhibitory potential with IC50 values ranging between 0.9 ± 0.01 to 46.4 ± 0.9 µM, under positive control of standard drug d-saccharic acid 1,4 lactone (IC50 = 48.1 ± 1.2 µM). Structural activity relationship (SAR) has been established for all synthesized compounds. To shed light on molecular interactions between the synthesized compounds and ß-glucuronidase, 1, 4, and 6 compounds were docked into the active binding site of ß-glucuronidase. The obtained results showed that this binding is thermodynamically favorable and ß-glucuronidase inhibition of the selected compounds increases with the number of hydrogen bonding established in selected compound-ß-glucuronidase complexes.

Synthesis of Thymidine Phosphorylase Inhibitor Based on Quinoxaline Derivatives and Their Molecular Docking Study.

We have synthesized quinoxaline analogs (1⁻25), characterized by ¹H-NMR and HREI-MS and evaluated for thymidine phosphorylase inhibition. Among the series, nineteen analogs showed better inhibition when compared with the standard inhibitor 7-Deazaxanthine (IC50 = 38.68 ± 4.42 µM). The most potent compound among the series is analog 25 with IC50 value 3.20 ± 0.10 µM. Sixteen analogs 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 21 and 24 showed outstanding inhibition which is many folds better than the standard 7-Deazaxanthine. Two analogs 8 and 9 showed moderate inhibition. A structure-activity relationship has been established mainly based upon the substitution pattern on the phenyl ring. The binding interactions of the active compounds were confirmed through molecular docking studies.

Synthesis, molecular docking study and in vitro thymidine phosphorylase inhibitory potential of oxadiazole derivatives.

We have synthesized oxadiazole derivatives (1-16), characterized by 1H NMR, 13C NMR and HREI-MS and screened for thymidine phosphorylase inhibitory potential. All derivatives display varied degree of thymidine phosphorylase inhibition in the range of 1.10 ±â€¯0.05 to 49.60 ±â€¯1.30 µM when compared with the standard inhibitor 7-Deazaxanthine having an IC50 value 38.68 ±â€¯1.12 µM. Structure activity relationships (SAR) has been established for all compounds to explore the role of substitution and nature of functional group attached to the phenyl ring which applies imperious effect on thymidine phosphorylase activity. Molecular docking study was performed to understand the binding interaction of the most active derivatives with enzyme active site.

Synthesis, SAR elucidations and molecular docking study of newly designed isatin based oxadiazole analogs as potent inhibitors of thymidine phosphorylase.

Thymidine phosphorylase is an enzyme involved in pyrimidine salvage pathway that is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is enormously up regulated in a variety of solid tumors. Furthermore, surpassing of TP level protects tumor cells from apoptosis and helps cell survival. Thus TP is identified as a prime target for developing novel anticancer therapies. A new class of exceptionally potent isatin based oxadiazole (1-30) has been synthesized and evaluated for thymidine phosphorylase inhibitory potential. All analogs showed potent thymidine phosphorylase inhibition when compared with standard 7-Deazaxanthine, 7DX (IC50 = 38.68 ±â€¯1.12 µM). Molecular docking study was performed in order to determine the binding interaction of these newly synthesized compounds, which revealed that these synthesized compounds established stronger hydrogen bonding network with active site of residues as compare to the standard compound 7DX.

Discovering phenoxy acetohydrazide derivatives as urease inhibitors and molecular docking studies.

Helicobacter pylori causes severe stomach disorders and the use of enzyme inhibitors for treatment is one of the possible therapies. The great biological potential of imine analogs as urease inhibitors has been the focus of researchers in past years. In this regard, we have synthesized twenty-one derivatives of dichlorophenyl hydrazide. These compounds were characterized by different spectroscopic techniques i.e. NMR and HREI-MS. Compounds 2 and 10 were found to be the most active in the series. Structure-activity relationship has been established for all compounds based on different substituents attached to the phenyl ring that play a vital role in enzyme inhibition. From the structure-activity relationship, it has been observed that these analogs showed excellent potential for urease and can be an alternate therapy in the future. The molecular docking study was performed to further explore the binding interactions of synthesized analogs with enzyme active sites.Communicated by Ramaswamy H. Sarma.

Synthesis of thiazole-based-thiourea analogs: as anticancer, antiglycation and antioxidant agents, structure activity relationship analysis and docking study.

This work reports the convenient approach for the synthesis of thiazole based thiourea derivatives (1-21) from 2-bromo-1-(4-fluorophenyl)thiazole-1-one and phenyl isothiocyanates. The scope and diversity were achieved from readily available phenyl isothiocyanates. This protocol involves an oxidative C-S bond formation. Moreover, hybrid thiazole based thiourea scaffolds (1-21) according to literature known protocol were screened in vitro for anticancer Potential against breast cancer, antiglycation and antioxidant inhibitory profile. All newly developed scaffolds were showed moderate to good inhibitory potentials ranging from 0.10 ± 0.01 µM to 11.40 ± 0.20 µM, 64.20 ± 0.40 µM to 385.10 ± 1.70 µM and 8.90 ± 0.20 µM to 39.20 ± 0.50 µM against anticancer, antiglycation and antioxidant respectively. Among the series, compounds 12 (IC50 = 0.10 ± 0.01 µM), 10 (IC50 = 64.20 ± 0.40 µM) and 12 (IC50 = 8.90 ± 0.20 µM) with flouro substitution at phenyl ring of thiourea were identified to be the most potent among the series having excellent anticancer, antiglycation and antioxidant potential. The structure of all the newly synthetics scaffolds were confirmed by using different types of spectroscopic techniques such as HREI-MS, 1H- and 13C-NMR spectroscopy. To find structure-activity relationship, molecular docking studies were carried out to understand the binding mode of active inhibitors with active site of enzymes and results supported the experimental data.Communicated by Ramaswamy H. Sarma.

Synthesis of indole derivatives as Alzheimer inhibitors and their molecular docking study.

Acetylcholinesterase prevails in the healthy brain, with butyrylcholinesterase reflected to play a minor role in regulating brain acetylcholine (ACh) levels. However, BuChE activity gradually increases in patients with (AD), while AChE activity remains unaffected or decays. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioural, and global functioning characteristic of AD. Current study described the synthesis of indole-based sulfonamide derivatives (1-23) and their biological activity. Synthesis of these scaffolds were achieved by mixing chloro-substituted indole bearing amine group with various substituted benzene sulfonyl chloride in pyridine, under refluxed condition to obtained desired products. All products were then evaluated for AchE and BuchE inhibitory potential compare with positive Donepezil as standard drug for both AchE and BchE having IC50 = 0.016 ± 0.12 and 0.30 ± 0.010 µM respectively. In this regard analog 9 was found potent having IC50 value 0.15 ± 0.050 µM and 0.20 ± 0.10 for both AchE and BuChE respectively. All other derivatives also found with better potential. All compounds were characterized by various techniques such as 1H, 13C-NMR and HREI-MS. In addition, biological activity was maintained to explore the bioactive nature of scaffolds and their protein-ligand interaction (PLI) was checked through molecular docking study.Communicated by Ramaswamy H. Sarma.

Therapeutic effect of Thymoquinone on behavioural response to UCMS and neuroinflammation in hippocampus and amygdala in BALB/c mice model.

RATIONALE: Major depressive disorder is the leading cause of disability worldwide. The corticolimbic system plays a critical role in the emotional and cognitive aspects of major depressive disorder. Owing to the unsatisfactory efficacy of conventional antidepressants, there is a need to explore novel therapies. OBJECTIVES: The current study aimed to explore the antidepressant potential of thymoquinone, a natural compound with anti-inflammatory activity, and propose its underlying mechanism of action in the unpredictable chronic mild stress (UCMS) mouse model. METHODS: Coat state, forced swim test, elevated plus maze test, novelty suppressed feeding test and social interaction test were performed to quantify the behavioural shift induced by UCMS and the effect of thymoquinone and fluoxetine treatment. In addition, messenger RNA (mRNA) expression levels of inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and BDNF and NeuN were analysed by a quantitative real-time polymerase chain reaction in the hippocampus and amygdala of experimental and control groups. RESULTS: UCMS significantly deteriorated coat state. Thymoquinone reinstated the resignation behaviour and latency to feed affected by UCMS. UCMS induced an increase in inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in the hippocampus and amygdala, which was decreased by thymoquinone. UCMS caused an increase in BDNF and NeuN mRNA levels in the amygdala while a decrease in the hippocampus. This opposite effect on BDNF was also compensated by thymoquinone; however, thymoquinone did not significantly change Ki67 and NeuN mRNA levels in the hippocampus. CONCLUSIONS: Thymoquinone restored the behavioural changes induced by UCMS. In addition, the antidepressant effect of thymoquinone is in line with changes in inflammatory parameters and changes in BDNF in the hippocampus and amygdala.

Varied Composition and Underlying Mechanisms of Gut Microbiome in Neuroinflammation.

The human gut microbiome has been implicated in a host of bodily functions and their regulation, including brain development and cognition. Neuroinflammation is a relatively newer piece of the puzzle and is implicated in the pathogenesis of many neurological disorders. The microbiome of the gut may alter the inflammatory signaling inside the brain through the secretion of short-chain fatty acids, controlling the availability of amino acid tryptophan and altering vagal activation. Studies in Korea and elsewhere highlight a strong link between microbiome dynamics and neurocognitive states, including personality. For these reasons, re-establishing microbial flora of the gut looks critical for keeping neuroinflammation from putting the whole system aflame through probiotics and allotransplantation of the fecal microbiome. However, the numerosity of the microbiome remains a challenge. For this purpose, it is suggested that wherever possible, a fecal microbial auto-transplant may prove more effective. This review summarizes the current knowledge about the role of the microbiome in neuroinflammation and the various mechanism involved in this process. As an example, we have also discussed the autism spectrum disorder and the implication of neuroinflammation and microbiome in its pathogenesis.

Synthesis of new urease enzyme inhibitors as antiulcer drug and computational study.

In search of potent urease inhibitor indole analogues (1-22) were synthesized and evaluated for their urease inhibitory potential. All analogues (1-22) showed a variable degree of inhibitory interaction potential having IC50 value ranging between 0.60 ± 0.05 to 30.90 ± 0.90 µM when compared with standard thiourea having IC50 value 21.86 ± 0.90 µM. Among the synthesized analogues, the compounds 1, 2, 3, 5, 6, 8, 12, 14, 18, 20 and 22 having IC50 value 3.10 ± 0.10, 1.20 ± 0.10, 4.60 ± 0.10, 0.60 ± 0.05, 5.30 ± 0.20, 2.50 ± 0.10, 7.50 ± 0.20, 3.90 ± 0.10, 3.90 ± 0.10, 2.30 ± 0.05 and 0.90 ± 0.05 µM respectively were found many fold better than the standard thiourea. All other analogues showed better urease interaction inhibition. Structure activity relationship (SAR) has been established for all analogues containing different substituents on the phenyl ring. To understand the binding interaction of most active analogues with enzyme active site docking study were performed.Communicated by Ramaswamy H. Sarma.

Thymoquinone harbors protection against Concanavalin A-induced behavior deficit in BALB/c mice model.

Global health estimates indicated approximately 322 million people living with depression. Rising cost of depressive illness treatment and non-responsiveness to existing therapies demand continued research to explore new and more potent therapies. Exploring the potential of natural compounds for their potent antidepressant potentials is becoming topic of interest for scientists. Anti-inflammatory activity of thymoquinone, the active ingredient of Nigella sativa, has been well documented. Current study tested thymoquinone for its antidepressant effect in a Concanavalin A (Con A)-induced depressive-like behavior in BALB/c mice. Thymoquinone successfully protected against Con A-induced behavioral despair and anxiety-like behavior. Reduced grooming behavior as a function of Con A treatment, was also reinstated. Underlying mechanism responsible for antidepressant activity of thymoquinone was analyzed by molecular docking. Thymoquinone interacts in halogen-binding pocket (HBP) of serotonin reuptake transporter indicating its potential as serotonin reuptake inhibitor. Results of current study anticipate thymoquinone as a potential antidepressant drug candidate. PRACTICAL APPLICATIONS: Black seeds of Nigella sativa are consumed with traditional and religious reference since centuries. Thymoquinone, active, and abundant component of Nigella sativa, has shown positive effects in multiple studies against arthritis, asthma, hepatic injury, neurodegeneration, and cancer owing to its immunomodulatory and anti-inflammatory attributes. Considering inflammation as one of central components involved in pathophysiology of major depressive disorder, thymoquinone has been evaluated in current study for its antidepressant potential. Positive results of current study propose thymoquinone as an affordable, natural antidepressant drug candidate with better safety profile than currently available antidepressant regimes. Thymoquinone might provide benefits against inflammation-related sickness behavior that is associated with poorer outcome of clinical depression, thus, paving the way for effective drug development against treatment-resistant depression.

Fabrication and Assessment of Diosgenin Encapsulated Stearic Acid Solid Lipid Nanoparticles for Its Anticancer and Antidepressant Effects Using in vitro and in vivo Models.

Inflammatory cascade plays a pivotal role in the onset and progression of major depressive disorder (MDD) and glioblastoma multiforme (GBM). Therefore, questing natural compounds with anti-inflammatory activity such as diosgenin can act as a double-edged sword targeting cancer and cancer-induced inflammation simultaneously. The blood-brain barrier limits the therapeutic efficiency of the drugs against intracranial pathologies including depression and brain cancers. Encapsulating a drug molecule in lipid nanoparticles can overcome this obstacle. The current study has thus investigated the anticancer and antidepressant effect of Tween 80 (P80) coated stearic acid solid lipid nanoparticles (SLNPs) encapsulating the diosgenin. Physio-chemical characterizations of SLNPs were performed to assess their stability, monodispersity, and entrapment efficiency. In vitro cytotoxic analysis of naked and drug encapsulated SLNPs on U-87 cell line indicated diosgenin IC50 value to be 194.4 µM, while diosgenin encapsulation in nanoparticles slightly decreases the toxicity. Antidepressant effects of encapsulated and non-encapsulated diosgenin were comprehensively evaluated in the concanavalin-A-induced sickness behavior mouse model. Behavior test results indicate that diosgenin and diosgenin encapsulated nanoparticles significantly alleviated anxiety-like and depressive behavior. Diosgenin incorporated SLNPs also improved grooming behavior and social interaction as well as showed normal levels of neutrophils and leukocytes with no toxicity indication. In conclusion, diosgenin and diosgenin encapsulated solid lipid nanoparticles proved successful in decreasing in vitro cancer cell proliferation and improving sickness behavioral phenotype and thus merit further exploration.

Exploring indole-based-thiadiazole derivatives as potent acetylcholinesterase and butyrylcholinesterase enzyme inhibitors.

Indole based thiadiazole derivatives (1-18) were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The IC50 values of the synthesized analogues ranging between 0.17 ± 0.05 to 33.10 ± 0.6 µM against (AChE) and 0.30 ± 0.1 to 37.60 ± 0.6 µM against (BChE) enzymes. Among the series compounds 8 (IC50 = 0.17 ± 0.05 µM) (IC50 = 0.30 ± 0.1 µM), 9 (IC50 = 0.30 ± 0.05 µM) (IC50 = 0.60 ± 0.05 µM) and 10 (IC50 = 1.30 ± 0.1 µM) (IC50 = 2.60 ± 0.1) were found to be the most potent analogues bearing para, ortho, and meta-fluoro substitutions on phenyl ring attached to thiadiazole. In addition, all the synthesized scaffolds were characterized by using 1H NMR, 13C NMR spectroscopy, and high-resolution Mass Spectrometry (HR-MS). To apprehend the binding mode of interaction of the most potent synthesized derivatives, a molecular docking study was performed.

Research Productivity in the Health Sciences in Saudi Arabia: 2008-2017.

The purpose of this study was to analyze the published research on health sciences carried out by researchers in Saudi Arabia in the last decade by assessing bibliometric output. Data for 2008 to 2017 was retrieved from Scopus. During this period, there was significant growth, from 1332 publications in 2008 to 5529 in 2017, with an average annual growth rate of 14.1%. King Saud University was the most productive institution. Most of the published research was done in collaboration with Egypt. The subject area of medicine was predominant with the main publication source being the Saudi Medical Journal, Life Science Journal, the Acta Zhengzhou University Oversea Version, and the Annals of Saudi Medicine, primarily in the form of original research articles. The growing trend in publications is a sign of the increasing quality of education and more research and development activities, which are made possible by a sufficient budget allocation to these activities during the last decade.

Synthesis, in vitro urease inhibitory potential and molecular docking study of benzofuran-based-thiazoldinone analogues.

In continuation of our work on enzyme inhibition, the benzofuran-based-thiazoldinone analogues (1-14) were synthesized, characterized by HREI-MS, 1H and 13CNMR and evaluated for urease inhibition. Compounds 1-14 exhibited a varying degree of urease inhibitory activity with IC50 values between 1.2 ± 0.01 to 23.50 ± 0.70 µM when compared with standard drug thiourea having IC50 value 21.40 ± 0.21 µM. Compound 1, 3, 5 and 8 showed significant inhibitory effects with IC50 values 1.2 ± 0.01, 2.20 ± 0.01, 1.40 ± 0.01 and 2.90 ± 0.01 µM respectively, better than the rest of the series. A structure activity relationship (SAR) of this series has been established based on electronic effects and position of different substituents present on phenyl ring. Molecular docking studies were performed to understand the binding interaction of the compounds.

Expiry of a completely splenectomised calf in post-operative period due to mixed piroplasm infection: a case report.

Bovine babesiosis is an infectious protozoan disease and causes significant economic losses in terms of production loss and mortality. The genus Babesia belongs to the family Babesiidae order piroplasmida and is transmitted by ticks globally. The signs of disease are particularly prominent in old or immuno-compromised animals. The spleen plays a vital role in defence against hemoparasites like Babesia. A young cross-bred cow calf of about 3 months of age was splenectomised to propagate Babesia in vivo experimentally. Prior to splenectomy, the calf was examined through microscopy and PCR analysis and was found negative for any kind of piroplasms including Babesia. The calf was completely splenectomised, but the calf was naturally infected during its postoperative period. The calf expired after naturally acquiring Babesia bigemina and Theileria annulata during the 11 th day of postoperative period owing to increased parasitaemia, exhibiting typical mixed parasitic infection stigmata e.g. reddish urine, elevated temperature up to 41.38°C. This study concluded that complete splenectomy along with dexamethasone administration in the postop period caused exceptional increase in parasitaemia. This parasitaemia couldn't be countered by any symptomatic treatment because of the absence of spleen and greatly reduced immunity of the animal.

Functional connectivity underpinnings of electroconvulsive therapy-induced memory impairments in patients with depression.

Electroconvulsive therapy (ECT) is an effective treatment for severe medication-resistant depression. However, ECT frequently results in episodic memory impairments, causing many patients to discontinue treatment. The objective of this study was to explore the functional connectivity underpinnings of ECT-induced episodic memory impairments. We investigated verbal episodic memory and intrinsic functional connectivity in 24 patients with depression (13F, 11M) before and after ECT, and 1 month after treatment. We used a novel individual-oriented approach to examine functional connectivity, and trained a linear support vector regression model to estimate verbal memory performance based on connectivity. The model identified a set of brain connections that can predict baseline verbal memory performance (r = 0.535, p = 0.026). Importantly, we found a nonoverlapping set of brain connections whose changes after ECT can track patients' verbal memory impairments (r = 0.613, p = 0.008). These connections mainly involve the frontoparietal control, default mode, and hippocampal networks, suggesting that ECT affects broad functional networks that are involved in memory performance. In contrast, functional connectivity defined using traditional group-level analyses was unable to estimate either baseline memory performance or post-ECT verbal memory impairments. A parallel analysis using the same strategy did not identify a connectivity marker for overall mood improvement, suggesting that functional connectivity changes related to depressive symptoms may be highly heterogenous. Our findings shed light on the mechanism through which ECT impairs episodic memory, and additionally underline the importance of accounting for interindividual variability in the investigation of functional brain organization in patients with depression.