Deep Learning Classifies Low- and High-Grade Glioma Patients with High Accuracy, Sensitivity, and Specificity Based on Their Brain White Matter Networks Derived from Diffusion Tensor Imaging.

Classifying low-grade glioma (LGG) patients from high-grade glioma (HGG) is one of the most challenging tasks in planning treatment strategies for brain tumor patients. Previous studies derived several handcrafted features based on the tumor's texture and volume from magnetic resonance images (MRI) to classify LGG and HGG patients. The accuracy of classification was moderate. We aimed to classify LGG from HGG with high accuracy using the brain white matter (WM) network connectivity matrix constructed using diffusion tensor tractography. We obtained diffusion tensor images (DTI) of 44 LGG and 48 HGG patients using routine clinical imaging. Fiber tractography and brain parcellation were performed for each patient to obtain the fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity weighted connectivity matrices. We used a deep convolutional neural network (DNN) for classification and the gradient class activation map (GRAD-CAM) technique to identify the neural connectivity features focused on by the DNN. DNN could classify both LGG and HGG with 98% accuracy. The sensitivity and specificity values were above 0.98. GRAD-CAM analysis revealed a distinct WM network pattern between LGG and HGG patients in the frontal, temporal, and parietal lobes. Our results demonstrate that glioma affects the WM network in LGG and HGG patients differently.

Synthesis of novel cytotoxic tetracyclic acridone derivatives and study of their molecular docking, ADMET, QSAR, bioactivity and protein binding properties.

Acridone based synthetic and natural products with inherent anticancer activity advancing the research and generating a large number of structurally diversified compounds. In this sequence we have designed, synthesized a series of tetracyclic acridones with amide framework viz., 3-(alkyloyl/ aryloyl/ heteroaryloyl/ heteroaryl)-2,3-dihydropyrazino[3,2,1-de]acridin-7(1H)-ones and screened for their in vitro anti-cancer activity. The in vitro study revealed that compounds with cyclopropyl-acetyl, benzoyl, p-hydroxybenzoyl, p-(trifluoromethyl)benzoyl, p-fluorobenzoyl, m-fluorobenzoyl, picolinoyl, 6-methylpicolinoyl and 3-nicotinoyl groups are active against HT29, MDAMB231 and HEK293T cancer cell lines. The molecular docking studies performed for them against 4N5Y, HT29 and 2VWD revealed the potential ligand-protein binding interactions among the neutral aminoacid of the enzymes and carbonyl groups of the title compounds with a binding energy ranging from - 8.1394 to - 6.9915 kcal/mol. In addition, the BSA protein binding assay performed for them has confirmed their interaction with target proteins through strong binding to BSA macromolecule. The additional studies like ADMET, QSAR, bioactivity scores, drug properties and toxicity risks ascertained them as newer drug candidates. This study had added a new collection of piperazino fused acridone derivatives to the existing array of other nitrogen heterocyclic fused acridone derivatives as anticancer agents.

MG17, A Novel Triazole Derivative Abrogated Neuroinflammation and Related Neurodegenerative Symptoms in Rodents.

BACKGROUND AND OBJECTIVE: The objective of present study is to explore multiple effects of the compound MG17 and relate them to achieve better therapeutic potential against neuroinflammation related disorders. We examined whether our compound is acting through regulating neuroinflammatory mediators. METHODS: We have done some preliminary behavioral studies to shortlist the derivatives using rodent models of peripheral nerve injury in our earlier publication and now we extended our screening studies to explore the test compounds efficacy on other related peripheral neurological disorders such as Streptozotocin- induced diabetic peripheral neuropathy (DPN) and methyl mercury (MeHg) induced neurodegeneration in rats. Pro-inflammatory cytokines interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were quantified with RT-qPCR studies and histopathology studies were performed taking tissue samples from MeHg induced neurodegeneration rats. The effect of MG17 was assessed on local and acute inflammation through carrageenan-induced rat paw edema model. RESULTS: We observed the reduction in nociceptive responses in DPN rats. Pain threshold was reduced greater than 50% in various pain assessment modules. Upregulated pro-inflammatory cytokines which are thought to have a prominent role in neuroinflammation was controlled near to normal level quantified by RT-PCR studies. However, MG17 was able to regulate IL-6 and TNF-α but not IL-1ß. CONCLUSION: Our results clearly suggest the beneficial potential of compound MG17 through inhibition of pro-inflammatory cytokines upregulation. MG17 could be an intriguing therapeutic approach in diabetesrelated neuro-pathophysiological conditions.

Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines.

A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar -NH2 group, 10f/11f having polar -OH group on phenyl ring displayed 3-4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.

Synthesis, molecular modeling and biological evaluation of aza-flavanones as α-glucosidase inhibitors.

An efficient acid catalyzed methodology has been employed to synthesize a variety of aza-flavanones and their α-glucosidase inhibitory activity is evaluated using acarbose, miglitol and voglibose as reference standards. Molecular modeling studies were performed for all compounds to identify the important binding modes responsible for the inhibition activity of α-glucosidase which helped find key interactions between the enzyme and the active compounds. Among all the compounds 5g, 5r and 5w have shown high α-glucosidase inhibition activity compared to standard reference drugs and have been identified as promising potential antidiabetic agents. This study is the first biological evaluation of aza-flavanones as α-glucosidase inhibitors.

Synthesis, molecular properties prediction and anticancer, antioxidant evaluation of new edaravone derivatives.

A series of new edaravone derivatives 3-7 have been synthesized, characterised using various spectroscopic techniques and screened for their in vitro anti-cancer, antioxidant activities. Structure of 5d was further substantiated through single crystal X-ray diffraction. Among the tested, 5l exhibited pronounced activity against PC3 cancer cells. Compounds 5i, 5l, 7c showed potent activity against A549 cancer cells. Products 5k, 6, 7c demonstrated good antioxidant activity with MIC values of 18.60, 16.27, 16.07µg/mL respectively. Further the reported analogues were also tested on normal HEK293T cells and displayed low to good safer profiles. Derivatives 5l and 7c have come out to be safer potent anticancer, antioxidant agents. Additionally, the target products were subjected to their molecular properties prediction and drug likeness by employing Molinspiration and Osiris property explorer toolkits. None of them violated Lipinski's boundaries classifying the title compounds as potential anticancer and antioxidant agents.

Design and Development of Mycobacterium tuberculosis Lysine ɛ-Aminotransferase Inhibitors for Latent Tuberculosis Infection.

Lysine ɛ-aminotransferase (LAT) is a protein involved in lysine catabolism, and it plays a significant role during the persistent/latent phase of Mycobacterium tuberculosis (MTB), as observed by its up-regulation by ~40-fold during this stage. We have used the crystal structure of MTB LAT in external aldimine form in complex with its substrate lysine as a template to design and identify seven lead compounds with IC50 ranging from 18.06 to > 90 µm. We have synthesized 21 compounds based on the identified lead, and compound 21 [2,2'-oxybis(N'-(4-fluorobenzylidene)acetohydrazide)] was found to be the most active with MTB LAT IC50 of 0.81 ± 0.03 µm. Compound 21 also showed a 2.3 log reduction in the nutrient-starved MTB model and was more potent than standard isoniazid and rifampicin at the same dose level of 10 µg/mL.

Synthesis, in vitro anticancer and antimycobacterial evaluation of new 5-(2,5-dimethoxyphenyl)-1,3,4-thiadiazole-2-amino derivatives.

A series of 2,5-disubstituted-1,3,4-thiadiazole derivatives 5a-5l, 7a-7e and 9 have been synthesised and screened for in vitro antimycobacterial activity against Mycobacterium smegmatis MC-155. In addition these compounds have also been screened for cytotoxic activity against cancer cell lines HT-29, MDA-MB-231 by MTT colorimetric assay. The compounds are well characterized by spectral analysis viz. (1)H NMR, (13)C NMR, FT-IR, mass and HRMS. Screening results indicate that compounds 5g, 7a possess good antitubercular activity with MIC value 65.74 and 40.86, respectively, compounds 5g, 7a, 7b, 7d, 7e and 9 displayed promising cytotoxic activity against the cell lines tested. 5g and 7a stand out to be potent antimycobacterial and anticancer agents among the tested series. Further the title compounds were also tested on human normal cells HEK293T and are found to be safer with lesser cytotoxicity. It is interesting to observe that compound 5g has come out to be safer, potent anticancer and antimycobacterial agent.

A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro.

PURPOSE: Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance to conventional chemotherapy and radiation, thereby implicating this kinase as a therapeutic intervention point. A novel scaffold of Akt inhibitors was developed through virtual screening of chemical databases available at Birla Institute of Technology and Science, Pilani, Hyderabad, based on docking studies using Maestro. A benzothienopyrimidine derivative (BIA-6) was identified as a potential lead molecule that inhibited Akt1 enzyme activity with an IC50 of 256 nM. MATERIALS AND METHODS: BIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transfer kit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170 cell lines. The effect of the compound on p-Akt (S(473)) was estimated. RESULTS: BIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a half maximal growth inhibition (GI50) range of 0.49 µM to 6.6 µM. Cell cycle analysis indicated that BIA-6 caused a G1 phase arrest at < 100 nM but led to apoptosis at higher doses. BIA-6 also exhibited synergism with standard chemotherapeutic agents. CONCLUSION: BIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer cell lines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high margin selectivity towards normal cells.

Design of dual inhibitors of ROCK-I and NOX2 as potential leads for the treatment of neuroinflammation associated with various neurological diseases including autism spectrum disorder.

Inhibition of both Rho kinase (ROCK-I) and NADPH oxidase (NOX2) to treat neuroinflammation could be very effective in the treatment of progressive neurological diseases like Alzheimer's disease, autism spectral disorder, and fragile X syndrome. NOX2 being a multi-enzyme component is activated during host defense in phagocytes such as microglia, to catalyze the production of superoxide from oxygen, while ROCK is an important mediator of fundamental cell processes like adhesion, proliferation and migration. Phosphorylated ROCK was found to activate NOX2 assembly via Ras related C3 botulinum toxin substrate (Rac) in disease conditions. Overexpression of ROCK-I and NOX2 in innate immune cells like microglial cells contribute to progressive neuronal damage early in neurological disease development. In the present study we employed a computer-aided methodology combining pharmacophores and molecular docking to identify new chemical entities that could inhibit ROCK-I as well as NOX2 (p47 phox). Among the huge dataset of a commercial database, top 18 molecules with crucial binding interactions were selected for biological evaluation. Seven among the lead molecules exhibited inhibitory potential against ROCK-I and NOX2 with IC50s ranging from 1.588 to 856.2 nM and 0.8942 to 10.24 µM, respectively, and emerged as potential hits as dual inhibitors with adequate selectivity index (SI = CC50/GIC50) in cell-based assays. The most active compound 3 was further found to show reduction of the pro-inflammatory mediators such as TNFα, interleukin-6 (IL-6) and interleukin-1beta (IL-1ß) mRNA expression levels in activated (MeHg treated) human neuroblastoma (IMR32) cell lines. Hence the present work documented the utility of these dual inhibitors as prototypical leads to be useful for the treatment of neurological disorders including autism spectrum disorder and Alzheimer's disease.

Design, synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives.

A novel synthesis of highly substituted pyrrole-N-acetic derivatives is described through the coupling of 1,4-diketones with amino acids following Paal-Knorr's approach. These pyrrole-N-acetic acid derivatives are found to exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q &5r are found to display excellent anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC values in the range of 2.97 µM. Conversely, these compounds showed low cytotoxicity (selectivity index: >16.83) against HEK-293T cell line.

A facile synthesis and discovery of highly functionalized tetrahydro-pyridines and pyridines as antimycobacterial agents.

The four-component reaction of ethyl-3-oxo-4-(arylsulfanyl)butanoate, substituted aromatic aldehydes and ammonium acetate afforded novel ethyl 4-hydroxy-2,6-diaryl-5-(arylsulfanyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylates. These tetrahydro-pyridine esters upon dehydrogenation with dichlorodicyanobenzoquinone (DDQ) afforded highly functionalized pyridines in excellent yields. These novel heterocycles were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv using agar dilution method. Among the compounds screened, ethyl 2,6-di(2-bromophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-pyridinecarboxylate was found to be the most active with a minimum inhibitory concentration of 1.33 microM against Mycobacterium tuberculosis and is 5.74 and 38.17 times more potent than the first line anti-tuberculosis (TB) drugs, ethambutol and pyrazinamide respectively.

N-methylisatin-beta-thiosemicarbazone derivative (SCH 16) is an inhibitor of Japanese encephalitis virus infection in vitro and in vivo.

BACKGROUND: During the early and mid part of 20th century, several reports described the therapeutic effects of N-methylisatin-beta-Thiosemicarbazone (MIBT) against pox viruses, Maloney leukemia viruses and recently against HIV. However, their ability to inhibit flavivirus replication has not been investigated. Hence the present study was designed to evaluate the antiviral activity of 14 MIBT derivatives against Flaviviruses that are prevalent in India such as Japanese Encephalitis Virus (JEV), Dengue-2 (Den-2) and West Nile viruses (WNV). RESULTS: Amongst the fourteen Mannich bases of MIBT derivatives tested one compound - SCH 16 was able to completely inhibit in vitro Japanese encephalitis virus (JEV) and West Nile virus (WNV) replication. However no antiviral activity of SCH 16 was noted against Den-2 virus replication. This compound was able to inhibit 50% of the plaques (IC50) produced by JEV and WNV at a concentration of 16 microgm/ml (0.000025 microM) and 4 microgm/ml (0.000006 microM) respectively. Furthermore, SCH 16 at a concentration of 500 mg/kg body weight administered by oral route twice daily was able to completely (100%) prevent mortality in mice challenged with 50LD50 JEV by the peripheral route. Our experiments to understand the mechanism of action suggest that SCH 16 inhibited JEV replication at the level of early protein translation. CONCLUSION: Only one of the 14 isatin derivatives -SCH 16 exhibited antiviral action on JEV and WNV virus infection in vitro. SCH 16 was also found to completely inhibit JEV replication in vivo in a mouse model challenged peripherally with 50LD50 of the virus. These results warrant further research and development on SCH 16 as a possible therapeutic agent.

Antimycobacterial and phototoxic evaluation of novel 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid.

Several newer 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids (10-11a-q) were synthesised from 3,4-difluoro aniline and 3-fluoro-4-nitro aniline by nine-step synthesis. The compounds were evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) as well as being tested for their ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesised compounds, 7-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-nitro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (11l) was found to be the most active compound in vitro, with minimum inhibitory concentrations (MICs) of 0.09 microM and <0.09 microM against MTB and MTR-TB, respectively. Compound 11l was found to be 4 times and >506 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model, 11l decreased the bacterial load in lung and spleen tissues by 30% and 42%, respectively, at a dose of 50 mg/kg body weight.

Microwave-assisted synthesis, anticonvulsant activity and quantum mechanical modelling of N-(4-bromo-3-methylphenyl) semicarbazones / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

<p><b>OBJECTIVE</b>To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics.</p><p><b>METHODS</b>A series of twenty-six compounds of N(4)-(4-bromo-3-methylphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Some potential compounds were also tested in the subcutaneous strychnine (scSTY) and subcutaneous picrotoxin (scPIC) seizure threshold tests. The synthesized compounds were tested for behavioral impairment and CNS (central nervous system) depression in mice. Quantum mechanical modelling was carried out on these compounds to gain understanding on the structural features essential for activity.</p><p><b>RESULTS</b>Some compounds possessed broad spectrum anticonvulsant activity as indicated by their effect in pentylenetetrazole, strychnine, picrotoxin and maximal electroshock seizures models in resemblance to other aryl semicarbazone derivatives reported earlier. The higher the difference in HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy levels was, the greater was the activity profile.</p><p><b>CONCLUSION</b>The pharmacophoric requirements for compounds to exhibit anticonvulsant activity that includes one aryl unit in proximity to a hydrogen donor-acceptor domain and an electron donor have been justified with the molecular orbital surface analysis of the synthesized compounds.</p>