Fractal dimension: analyzing its potential as a neuroimaging biomarker for brain tumor diagnosis using machine learning.

Purpose: The main purpose of this study was to comprehensively investigate the potential of fractal dimension (FD) measures in discriminating brain gliomas into low-grade glioma (LGG) and high-grade glioma (HGG) by examining tumor constituents and non-tumorous gray matter (GM) and white matter (WM) regions. Methods: Retrospective magnetic resonance imaging (MRI) data of 42 glioma patients (LGG, n = 27 and HGG, n = 15) were used in this study. Using MRI, we calculated different FD measures based on the general structure, boundary, and skeleton aspects of the tumorous and non-tumorous brain GM and WM regions. Texture features, namely, angular second moment, contrast, inverse difference moment, correlation, and entropy, were also measured in the tumorous and non-tumorous regions. The efficacy of FD features was assessed by comparing them with texture features. Statistical inference and machine learning approaches were used on the aforementioned measures to distinguish LGG and HGG patients. Results: FD measures from tumorous and non-tumorous regions were able to distinguish LGG and HGG patients. Among the 15 different FD measures, the general structure FD values of enhanced tumor regions yielded high accuracy (93%), sensitivity (97%), specificity (98%), and area under the receiver operating characteristic curve (AUC) score (98%). Non-tumorous GM skeleton FD values also yielded good accuracy (83.3%), sensitivity (100%), specificity (60%), and AUC score (80%) in classifying the tumor grades. These measures were also found to be significantly (p < 0.05) different between LGG and HGG patients. On the other hand, among the 25 texture features, enhanced tumor region features, namely, contrast, correlation, and entropy, revealed significant differences between LGG and HGG. In machine learning, the enhanced tumor region texture features yielded high accuracy, sensitivity, specificity, and AUC score. Conclusion: A comparison between texture and FD features revealed that FD analysis on different aspects of the tumorous and non-tumorous components not only distinguished LGG and HGG patients with high statistical significance and classification accuracy but also provided better insights into glioma grade classification. Therefore, FD features can serve as potential neuroimaging biomarkers for glioma.

An optimal brain tumor segmentation algorithm for clinical MRI dataset with low resolution and non-contiguous slices.

BACKGROUND: Segmenting brain tumor and its constituent regions from magnetic resonance images (MRI) is important for planning diagnosis and treatment. In clinical routine often an experienced radiologist delineates the tumor regions using multimodal MRI. But this manual segmentation is prone to poor reproducibility and is time consuming. Also, routine clinical scans are usually of low resolution. To overcome these limitations an automated and precise segmentation algorithm based on computer vision is needed. METHODS: We investigated the performance of three widely used segmentation methods namely region growing, fuzzy C means and deep neural networks (deepmedic). We evaluated these algorithms on the BRATS 2018 dataset by choosing randomly 48 patients data (high grade, n = 24 and low grade, n = 24) and on our routine clinical MRI brain tumor dataset (high grade, n = 15 and low grade, n = 28). We measured their performance using dice similarity coefficient, Hausdorff distance and volume measures. RESULTS: Region growing method performed very poorly when compared to fuzzy C means (fcm) and deepmedic network. Dice similarity coefficient scores for FCM and deepmedic algorithms were close to each other for BRATS and clinical dataset. The accuracy was below 70% for both these methods in general. CONCLUSION: Even though the deepmedic network showed very high accuracy in BRATS challenge for brain tumor segmentation, it has to be custom trained for the low resolution routine clinical scans. It also requires large training data to be used as a stand-alone algorithm for clinical applications. Nevertheless deepmedic may be a better algorithm for brain tumor segmentation when compared to region growing or FCM.

Identification of potent chromone embedded [1,2,3]-triazoles as novel anti-tubercular agents.

A series of 20 novel chromone embedded [1,2,3]-triazoles derivatives were synthesized via an easy and convenient synthetic procedure starting from 2-hydroxy acetophenone. The in vitro anti-mycobacterial evaluation studies carried out in this work reveal that seven compounds exhibit significant inhibition against Mycobacterium tuberculosis H37Rv strain with MIC in the range of 1.56-12.5 µg ml-1. Noticeably, compound 6s was the most potent compound in vitro with a MIC value of 1.56 µg ml-1. Molecular docking and chemoinformatics studies revealed that compound 6s displayed drug-like properties against the enoyl-acyl carrier protein reductase of M. tuberculosis further establishing its potential as a potent inhibitor.

Synthesis and biological evaluation of phaitanthrin congeners as anti-mycobacterial agents.

Natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) and its analogues are found to exhibit potent anti-tubercular activity against MDR-TB. A novel class of indolo[2,1-b]quinazolinones have been synthesized to evaluate their anti-mycobacterial activity. Enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis is one of the key enzymes and has been validated as an effective anti-microbial target. In silico molecular docking study demonstrates that the synthesized compounds exhibit high affinity for the M. tuberculosis drug target InhA. Phaitanthrin is a natural product, which belongs to a family of tryptanthrin and exhibits structural similarity except at position 6. Phaitanthrin derivatives are prepared by modifying the keto functionality of tryptanthrin. These phaitanthrin congeners are found to display promising anti-tubercular activity.

Pharmacophore-based 3DQSAR and molecular docking studies to identify new non-peptidic inhibitors of cathepsin S.

Cathepsin S (CatS) is one of the 11 cysteine protease cathepsins which are expressed predominantly in antigen presenting cells (APC) namely B cells, macrophages and dendritic cells. CatS has been implicated in a wide range of diseases such as rheumatoid arthritis, multiple sclerosis, neuropathic pain and allergic disorders. In the present study, pharmacophore mapping studies followed by 3D QSAR analysis was undertaken for a large set of 161 molecules reported to be non-covalent binding and non-peptidic inhibitors of CatS. The activity range (IC50) of these compounds was between 2 picomolar to 100 nanomolar. A five point pharmacophore model with three hydrogen bond acceptors (A), one hydrogen bond donor (D) and one hydrophobic (H) group as pharmacophoric features was developed. The generated model showed reasonable predictive power, with a correlation coefficient Q(2) of 0.607. The model was further confirmed by an external test-set validation that showed statistically significant parameters r(2) value of 0.840 with the R(2)p value of 0.812 and r(2)m value of 0.530. Validated model was then used to identify six diverse non-peptidic scaffolds from a commercial structure database by the analyses of parameters such as pharmacophore fitness, docking score, interacting amino acids and ADME properties to achieve prototypical lead compounds.

Synthesis and antitubercular activity of amino alcohol fused spirochromone conjugates.

A series of 21 new amino alcohol fused spirochromone conjugates have been synthesized, characterized with analytical data and evaluated their antimycobacterial activity against Mycobacterium tuberculosis (virulent strain H37Rv) in vitro. Some of the compounds exerted significant inhibition, in particular, compound 4f found to be the most potent derivative exhibiting MIC=3.13 µg/mL.

Combination of N-methylisatin-ß-thiosemicarbazone derivative (SCH16) with ribavirin and mycophenolic acid potentiates the antiviral activity of SCH16 against Japanese encephalitis virus in vitro.

AIM: To investigate the drug to drug interaction of N-methylisatin-ß-thiosemicarbazone (MIBT) derivative (SCH16) with ribavirin, mycophenolic acid and pentoxifylline against Japanese encephalitis virus in vitro. Our earlier studies have reported significant antiviral activity of these compounds against Japanese encephalitis virus in vitro and in vivo. METHODS AND RESULTS: An in vitro drug to drug combination analysis was carried out to investigate whether or not the direct antiviral effect shown by the individual MIBT derivative could be effectively increased when lower concentrations of two compounds in combination were used. The results of this study showed that the combination of MIBT derivative (SCH16) with ribavirin or mycophenolic acid significantly enhanced the antiviral activity of SCH16 against JEV in vitro. In contrast, the combination of SCH16 and pentoxifylline resulted in antagonism. CONCLUSION: The antiviral activity showed by SCH16 was enhanced in the presence of ribavirin and mycophenolic acid. SIGNIFICANCE AND IMPACT OF THE STUDY: Studying the synergistic/additive interaction of the compounds in combination would help in lowering the effective concentration so as to overcome the concern of toxicity.

Synthesis, structure-activity relationship of novel substituted 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents.

Series of 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 7a-7zb, 8a-8d and 9a-9d were synthesized and screened for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H(37)Rv (MTB) and cytotoxicity against three human cancer cell lines including A549, SK-N-SH and HeLa. The results indicate that six compounds are more potent and 7za is most effective anti-mycobacterial derivative compared to the standard drugs Ethambutol and Ciprofloxacin. However, 12 compounds exhibited cytotoxicity against human neuroblastoma cell line; amongst them the compound 7v is most effective compared to the standard drug Doxorubicin. This is the first report assigning in vitro anti-mycobacterial, anticancer and structure-activity relationship for this new class of 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates.

Novel phthalazinyl derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis isocitrate lyase enzyme.

Novel 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid hydrazones were synthesized from phthalic anhydride by a six step synthesis and evaluated for in vitro, in vivo activities against eight mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among twenty six compounds N'1-[(4-nitrophenyl)methylene]-2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-1,2,3,4-tetrahydro-1-phthalazinyl]ethanohydrazide (7j) was found to be the most active compound in-vitro with MIC's of 0.18 and <0.09 microM against log-phase cultures of MTB and multi-drug resistant MTB respectively. Compound 7j inhibited all the eight mycobacterial species with MIC ranging from <0.09-12.25 microM and was not toxic to Vero cell lines till 122.5 microM. Seven compounds were tested against starved culture of MTB and they inhibited with MIC's ranging from 2.88-8.91 microM. Some compounds showed 45-61% inhibition against MTB ICL enzyme at 10 microM. In the in vivo animal model 7j decreased the bacterial load in lung and spleen tissues with 1.87 and 3.03-log10 protections respectively at 25 mg/kg body weight dose.

Cyclization of the semicarbazone template of aryl semicarbazones: synthesis and anticonvulsant activity of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one.

A new series of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one were synthesized to study the effect of cyclization of the semicarbazone moiety of aryl semicarbazones on the anticonvulsant activity. Structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. All compounds were evaluated for their anticonvulsant activity in four animal models of seizures, viz. maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and subcutaneous picrotoxin (scPIC)-induced seizure threshold tests. The compounds were also evaluated for neurotoxicity. Compounds 4, 9, 14-19 exhibited anticonvulsant activity in all the four animal models of seizure.

Neuropathic pain: strategies in drug discovery and treatment.

Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. In contrast to acute nociceptive pain, the cascade of events that arise following peripheral nerve injury leads to a maintained abnormality in the sensory system, resulting in an abnormal pain phenomenon that can be grossly debilitating. At present, there are very few effective and well-tolerated therapies for neuropathic pain. The development of animal models and constant progress in the understanding of the basic pathophysiology of neuropathic pain has led to multifarious drug targets and treatment options. The most effective agents are use-dependent inhibitors of Na(+) channels, namely phenytoin, lamotrigine and carbamazepine. Owing to an effect of increase in the serotonin and various other biogenic amine levels on the pain modulating system, various classes of antidepressants including selective serotonin re-uptake inhibitors and selective noradrenaline re-uptake inhibitors are being used clinically. Modulation of Ca(2+) channels is another useful approach for the treatment of neuropathic pain. In particular, the modulation of N-type Ca((2+)) channels, which are expressed primarily in central and peripheral nervous tissues, has been the subject of greatest interest. In view of the above, this review discusses the various strategies and approaches to novel drug discovery and pharmacotherapy of neuropathic pain syndromes.

Synthesis and anti-HIV activity of nevirapine prodrugs.

The synthesis, in vitro anti-HIV activity and stability studies of the N-Mannich bases of nevirapine are reported. Among the synthesized compounds, 5-{[4-(4-chlorophenyl)piperazin-1 -yl]methyl}-1-cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido[2,3-e:3',2'-b][1,4]diazepin-6-one (3) was found to be the most potent compound with EC50 of 0.0159 microM against HIV-1 replication and CC50 of >1000 microM against CEM cell lines with selectivity index of >62893. Compound 3 was five times more active than nevirapine (EC50 of 0.09 microM). In vitro hydrolysis of the Mannich bases in phosphate buffer (pH 7.4) indicated that these agents were relatively stable with t1/2 ranging from 15 to 240 min.

Quantum mechanical modeling of N4-(2, 5-disubstituted phenyl) semicarbazones: synthesis and anticonvulsant activity of N4-(2, 5-dimethylphenyl/ -2-fluoro-5-methyl phenyl) semicarbazones.

Two new series of N4-(2, 5-disubstitutedphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in various animal models of seizures. Quantum mechanical modeling was carried out on these compounds to understand the structural features essential for activity. The higher the difference in HOMO and LUMO energy levels the greater was the activity profile. Substitution with fluoro group on the ortho position of the aryl ring was found to decrease the reactivity and hence the activity profile of aryl semicarbazones, which has been justified with the molecular orbital surface analysis of the synthesized compounds.

Synthesis and structure-activity relationship on anticonvulsant aryl semicarbazones.

Seven series of various substituted aryl semicarbazones were synthesized and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure threshold tests. A comprehensive structure-activity relationship was derived comparing the substituents on the aryl ring and in the carbimino terminal. Generally the order of activity was 4-F > 2-Br = 3-Br = 4-Cl > 4-CH(3) > 4-Br > 3-Cl > 3-CH(3) with respect to the primary aryl group. Most of the compounds exhibited activity both in the MES and scPTZ screens. The 4-fluorophenyl substituted semicarbazones (5a-5y) emerged as the most potent compounds exhibiting anticonvulsant activity in mouse intraperitoneal (i.p.) and rat per oral (p.o.) MES, scPTZ and psychomotor seizure (6 Hz) screens.

Synthesis, anti-HIV and antitubercular activities of isatin derivatives.

HIV is the most significant risk factor for many opportunistic infections like tuberculosis. In this study, we designed an isatinimino lead compound as a novel non-nucleoside reverse transcriptase inhibitor with antimycobacterial properties for the effective treatment of AIDS and AIDS-related tuberculosis. Among the compounds sythesized, 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7[[N4-[3'-[(4,6-dimethylpyrimidin-2-yl)benzenesulfonamido-4-yl]imino-1'-(5-fluoroisatinyl)]methyl]-3-methyl N1-piperazinyl]-3-quinoline carboxylic acid (9) emerged as the most potent broad-spectrum chemotherapeutic agent active against HIV (EC50: 12.1 microg/ml), and Mycobacterium tuberculosis (MIC: 1.22 microg/ml).

Synthesis of zidovudine prodrugs with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS.

A series of prodrugs of zidovudine has been synthesized in an effort to enhance spectrum of chemotherapeutic properties for the effective treatment of HIV/AIDS. The 5'-OH function of zidovudine was esterified with ciprofloxacin, norfloxacin, isoniazide, pyrazinamide acetic acid. The anti-HIV-1 activity of the esters was determined in CEM cell-line and zidovudine ester bearing pyrazinamide acetic acid was found to be the most potent compound with EC50 of<0.0636 microM, CC50 of>1000 microM and selectivity index (SI) of>15,723. Zidovudine prodrug bearing ciprofloxacin and norfloxacin moiety showed 100% inhibition against Mycobacterium tuberculosis H37Rv at 6.25 microg/ml. The prodrugs were also found to exhibit antibacterial activity against 24 pathogenic bacteria. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterase with t1/2 ranging from 20 to 240 min.

Newer aminopyrimidinimino isatin analogues as non-nucleoside HIV-1 reverse transcriptase inhibitors for HIV and other opportunistic infections of AIDS: design, synthesis and biological evaluation.

Human immuno deficiency virus (HIV) weakens the immune system so that many opportunistic infections (OIs) like tuberculosis, hepatitis, bacterial infections etc can develop. In this paper, we designed aminopyrimidinimino isatin lead compound as a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with broad-spectrum chemotherapeutic properties for the effective treatment of AIDS and AIDS-related OIs. Compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[[N4-[3'-(4'-amino-5'-trimethoxybenzyl pyrimidin-2'-yl)imino-1'-(5-methylisatinyl)]methyl]-N1-piperazinyl]-3-quinoline carboxylic acid (10) emerged as the most potent broad-spectrum chemotherapeutic agent active against HIV, HCV, Mycobacterium tuberculosis and various pathogenic bacteria.

The GABA shunt: an attractive and potential therapeutic target in the treatment of epileptic disorders.

Epilepsy is the most common primary neurological disorder known. Epileptiform neurons undergo paroxysmal depolarization shifts (PDS), which result in the excessive sustained neuronal firing seen in epilepsy. These shifts are due to either an impairment of GABA mediated inhibition, or an enhancement of aspartate or glutamate mediated excitatory transmission. Recent research has focused on the cellular biology of seizures. 4-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter of mammalian central nervous system. In neural and nonneural tissues, GABA is metabolized by three enzymes-glutamic acid decarboxylase (GAD), which produces GABA from glutamic acid, and the catabolic enzymes GABA-transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). Production of succinic acid by SSADH allows entry of the GABA carbon skeleton into the tricarboxylic acid cycle. GABA-T is present in a variety of circulating cells, including platelets and lymphocytes. SSADH, the final enzyme of GABA catabolism, has been detected in some of the tissues in which GAD and GABA-T have been identified. This paper is aimed at elucidating the organization of the GABA shunt and covers a review on the antiepileptic drugs, both established and currently under development targeted to the GABA shunt in order to bring about effective seizure control.