A Nano-Mgo and Ionic Liquid-Catalyzed ‘Green’ Synthesis Protocol for the Development of Adamantyl-Imidazolo-Thiadiazoles as Anti-Tuberculosis Agents Targeting Sterol 14α-Demethylase (CYP51)

In this work, we describe the ‘green’ synthesis of novel 6-(adamantan-1-yl)-2-substitutedimidazo[2,1-b][1,3,4]thiadiazoles (AITs) by ring formation reactions using 1-(adamantan-1-yl)-2-bromoethanone and 5-alkyl/aryl-2-amino1,3,4-thiadiazoles on a nano material base inionic liquid media. Given the established activity of imidazothiadiazoles against M. tuberculosis,we next examined the anti-TB activity of AITs against the H37Rv strain using Alamarblue assay. Among the tested compounds 6-(adamantan-1-yl)-2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole (3f) showed potent inhibitory activity towards M. tuberculosis with an MIC value of 8.5 μM. The inhibitory effect of this molecule against M. tuberculosis was comparable to the standard drugs such as Pyrazinamide, Streptomycin, and Ciprofloxacin drugs. Mechanistically, an in silico analysis predicted sterol 14α-demethylase (CYP51)as the likely target and experimental activity of 3f in this system corroborated the in silico target prediction. In summary, we herein report the synthesis and biological evaluation of novel AITs against M. tuberculosis that likely target CYP51 to induce their antimycobacterial activity

A nano-MgO and ionic liquid-catalyzed 'green' synthesis protocol for the development of adamantyl-imidazolo-thiadiazoles as anti-tuberculosis agents targeting sterol 14α-demethylase (CYP51)

In this work, we describe the 'green' synthesis of novel 6-(adamantan-1-yl)-2-substitutedimidazo2,1-b1,3,4thiadiazoles (AITs) by ring formation reactions using 1-(adamantan-1-yl)-2-bromoethanone and 5-alkyl/aryl-2-amino1,3,4-thiadiazoles on a nano material base in ionic liquid media. Given the established activity of imidazothiadiazoles against M. tuberculosis, we next examined the anti-TB activity of AITs against the H37Rv strain using Alamar blue assay. Among the tested compounds 6-(adamantan-1-yl)-2-(4-methoxyphenyl)imidazo2,1-b1,3,4thiadiazole (3f) showed potent inhibitory activity towards M. tuberculosis with an MIC value of 8.5 μM. The inhibitory effect of this molecule against M. tuberculosis was comparable to the standard drugs such as Pyrazinamide, Streptomycin, and Ciprofloxacin drugs. Mechanistically, an in silico analysis predicted sterol 14α-demethylase (CYP51) as the likely target and experimental activity of 3f in this system corroborated the in silico target prediction. In summary, we herein report the synthesis and biological evaluation of novel AITs against M. tuberculosis that likely target CYP51 to induce their antimycobacterial activity. © 2015 Anusha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Data-Driven Derivation of an "Informer Compound Set" for Improved Selection of Active Compounds in High-Throughput Screening.

Despite the usefulness of high-throughput screening (HTS) in drug discovery, for some systems, low assay throughput or high screening cost can prohibit the screening of large numbers of compounds. In such cases, iterative cycles of screening involving active learning (AL) are employed, creating the need for smaller "informer sets" that can be routinely screened to build predictive models for selecting compounds from the screening collection for follow-up screens. Here, we present a data-driven derivation of an informer compound set with improved predictivity of active compounds in HTS, and we validate its benefit over randomly selected training sets on 46 PubChem assays comprising at least 300,000 compounds and covering a wide range of assay biology. The informer compound set showed improvement in BEDROC($\alpha$ = 100), PRAUC, and ROCAUC values averaged over all assays of 0.024, 0.014, and 0.016, respectively, compared to randomly selected training sets, all with paired $t$-test p-values <10$^{-15}$. A per-assay assessment showed that the BEDROC($\alpha$ = 100), which is of particular relevance for early retrieval of actives, improved for 38 out of 46 assays, increasing the success rate of smaller follow-up screens. Overall, we showed that an informer set derived from historical HTS activity data can be employed for routine small-scale exploratory screening in an assay-agnostic fashion. This approach led to a consistent improvement in hit rates in follow-up screens without compromising scaffold retrieval. The informer set is adjustable in size depending on the number of compounds one intends to screen, as performance gains are realized for sets with more than 3,000 compounds, and this set is therefore applicable to a variety of situations. Finally, our results indicate that random sampling may not adequately cover descriptor space, drawing attention to the importance of the composition of the training set for predicting actives.The Netherlands Organisation for Scientific Research (Grant ID: NWO-017.009-065), Novartis Institutes for BioMedical Research, Prins Bernhard Cultuurfonds, European Research Commissio

Fetal polycystic kidney disease: Pathological overview

Polycystic kidney disease is a rare developmental anomaly inherited as autosomal dominant or autosomal recessive. It is characterized by cystic dilatation of the collecting ducts frequently associated with hepatic involvement and progression to renal failure. It is included in the differential diagnosis of cystic diseases of the kidney. We report a case of polycystic kidney disease, in 22 weeks fetus incidentally detected on routine antenatal ultrasonography and confirmed by fetal autopsy. This report elucidates the importance of early diagnosis and intervention in cystic kidney diseases

Novel benzoxazine-based aglycones block glucose uptake in vivo by inhibiting glycosidases

Glycoside hydrolases catalyze the selective hydrolysis of glycosidic bonds in oligosaccharides, polysaccharides, and their conjugates. β-glucosidases occur in all domains of living organisms and constitute a major group among glycoside hydrolases. On the other hand, the benzoxazinoids occur in living systems and act as stable β-glucosides, such as 2-(2,4-dihydroxy-7-methoxy- 2H-1,4-benzoxazin-3(4H)-one)-β-D-gluco-pyranose, which hydrolyse to an aglycone DIMBOA. Here, we synthesized the library of novel 1,3-benzoxazine scaffold based aglycones by using 2-aminobenzyl alcohols and aldehydes from one-pot reaction in a chloroacetic acid catalytic system via aerobic oxidative synthesis. Among the synthesized benzoxazines, 4-(7-chloro-2,4-dihydro-1H- benzod1,3oxazin-2-yl)phenol (compound 7) exhibit significant inhibition towards glucosidase compared to acarbose, with a IC50 value of 11.5 μM. Based upon results generated by in silico target prediction algorithms (Naïve Bayesian classifier), these aglycones potentially target the additional sodium/glucose cotransporter 1 (where a log likelihood score of 2.70 was observed). Furthermore, the in vitro glucosidase activity was correlated with the in silico docking results, with a high docking score for the aglycones towards the substrate binding site of glycosidase. Evidently, the in vitro and in vivo experiments clearly suggest an anti-hyperglycemic effect via glucose uptake inhibition by 4-(7-chloro-2,4-dihydro-1H-benzod1,3oxazin-2-yl)phenol in the starved rat model. These synthetic aglycones could constitute a novel pharmacological approach for the treatment, or re-enforcement of existing treatments, of type 2 diabetes and associated secondary complications. © 2014 Bharathkumar et al

Nano-MoO3-mediated synthesis of bioactive thiazolidin-4-ones acting as anti-bacterial agents and their mode-of-action analysis using in silico target prediction, docking and similarity searching

Medicinal Chemistr

Multidrug Resistant Non-Typhoidal Salmonella Infections

Over a period of 2 years, 28 patients admitted to Government General Hospital (GGH), Sangli (which is attached to Government Medical College (GMC), Miraj) yielded multi-drug resistant non-typhoidal salmonellae from their clinical material. The pediatric age group predominated in the study, accounting for 93% of cases. Salmonella typhimurium was the main isolate (86%), the other being Salmonella newport (14%). Gastroenteritis was the commonest presentation. Septicaemia was seen with 100% mortality, in infants below 1 month of age. Two cases of meningitis were also seen.</jats:p