Synthesis and antitubercular evaluation of 2-iminothiazolidine-4-ones

In the present manuscript, we report synthesis of new 3 and 5 substituted 2-imino thiazolidine-4-ones by three step synthetic protocols from 3-trifluormethyl aniline or 2-amino heterocycle. The compounds were evaluated for in vitro activities against Mycobacterium tuberculosis (MTB) in presence and absence of efflux pump inhibitor, cytotoxicity against RAW 264.7 cells. Among the thirty six compounds, 2-imino-3-(5-nitrothiazol-2-yl)-5-(3,4,5-trimethoxybenzylidene)thiazolidin-4-one (5g) was found to be the most active compound in vitro with MICs of 3.31 µM against log-phase culture of MTB and also non-toxic up to 100 µM. Compound 5g showed minimum inhibitory concentration (MIC) of 0.82 µM against MTB in presence of efflux pump inhibitor verapamil

Why human papilloma virus vaccination coverage is low among adolescents in the US? A study of barriers for vaccination uptake

Introduction: Cervical cancer and Human papillomavirus (HPV) affects women, men, and children of all races, ethnicities, and backgrounds. The objective of this study is to examine the association between adolescent (13–17 years) HPV vaccination uptake and the key factors influencing the uptake rates of HPV vaccination. Materials and Methods: The 2016 NIS-Teen data, an annual survey conducted by the CDC to monitor vaccination uptake in the United States is used for this study. Multivariable logistic regression model was used to estimate the relationship between various factors and HPV vaccine uptake. Results: Male adolescents were 0.26 times less likely to get the HPV vaccines; adolescents covered by private health insurance were 0.18 times less likely to get HPV vaccines; Hispanic adolescents were 1.47 times more likely, adolescents from other races including Asians were 1.75 times more likely to get vaccinated for HPV compared to non-Hispanic white adolescents. Adolescents from the low-income families were 1.21 times more likely to get vaccinated for HPV; adolescents from North-eastern regions of the United States were 1.62 times more likely to get vaccinated; adolescents who were not recommended for vaccination by the family physicians were 0.43 times less likely to get HPV vaccination; adolescents who did not have any safety concerns and concerns about side effects were 3.24 times more likely to get the HPV vaccine; adolescents from households that did have not orthodox religious beliefs were 13.67 times more likely to get vaccinated. Conclusions: Vaccination uptake rates are low for adolescents in the US and the results of this study identified important barriers which need to be addressed in order to improve vaccine uptake rates among the target groups which are less likely to get vaccinated. Also, knowing the sociodemographic and community level factors associated with HPV vaccination uptake status, health planners can better plan strategies to improve HPV vaccination in their local settings

Informed consent: A study of experiences and opinion of utilizers of health services from India

One hundred and forty-eight subjects drawn from urban and rural settings who had been hospitalized for any medical problem within the previous three years were interviewed using a semi structured interview schedule to understand their opinion and experiences of informed consent. Sixty medical officers providing primary care in both urban and rural areas were concurrently interviewed to gather their opinion. Results revealed that respondents were dissatisfied with the information they had received about the different aspects of their illness. Both the doctors and the patients felt the need for providing adequate information to utilizers of health services. The two groups identified certain constraints, like illiteracy, in obtaining informed consent. Doctors compared to patients more often thought that illiterates could not understand the information. Patients more often felt that information about nature of investigations and about prognosis need not be routinely revealed.informed consent experiences and opinion utilizers of health services India

Low-capacitance solid-state transformer control using an analytic filter

In the modular three-stage solid-state transformer (SST), each phase is integrated with large dc-link capacitors as energy buffers, to filter the second harmonic capacitor voltage ripple generated due to single-phase power processing. Although large dc-link capacitors reduce the coupling between stages of the SST and simplify the controller design, they compromise the reliability, safety and power density of the SST. Accordingly, a low-capacitance SST is desirable to address these challenges. To provide a high-bandwidth control for the low-capacitance SST, this paper proposes using an analytic filtering scheme rather than the low-pass filters used in conventional SST control schemes. A portion of the second harmonic power ripple in the high-voltage dc-link capacitors is processed by the SST’s dc-dc stage to facilitate the use of low capacitance. The effectiveness of the proposed control is demonstrated through a simulation study in PLECS.Submitted/Accepted versio

Investigating structure–activity relationship and mechanism of action of antitubercular 1-(4-chlorophenyl)-4-(4-hydroxy-3-methoxy-5-nitrobenzylidene) pyrazolidine-3,5-dione [CD59]

Background and objectives: The objective of this study is to synthesize and evaluate 1-(4-chlorophenyl)-4-(4-hydroxy-3-methoxy-5-nitrobenzylidene) pyrazolidine-3,5-dione (CD59) analogues to establish structure–activity relationship and mechanism of action. Methods: Thirty analogues of reported antitubercular CD59 were prepared by two-step synthetic protocols and characterized. The compounds were evaluated for in vitro activities against Mycobacterium tuberculosis (MTB), cytotoxicity against RAW 264.7 cells. The molecules were also evaluated for three mycobacterial enzymes to study the mechanism of action. Results: Among the compounds, 4-(2-bromobenzylidene)-1-(4-chlorophenyl)pyrazolidine-3,5-dione (4k) was found to be the most active compound in vitro with MICs of 4.13 μM against log-phase culture of MTB and also non-toxic up to 50 μM. Conclusions: Amongst all, the compounds 4g, 3i and 3n were most active against the enzymes MTB Pantothenate synthetase, lysine amino transferase and Alanine dehydrogenase, respectively. Further screening of these molecules was required in the in vitro dormant MTB models

Design and development of ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues as Mycobacterium tuberculosis ketol-acid reductoisomerase inhibitors

Based on our previous finding that the titled compound possesses anti-tuberculosis activity, a series of novel ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues have been synthesized. Amongst the 22 compounds synthesized and tested, 5b, 5c and 6c showed potent inhibitory activity with K values of 2.02, 5.48 and 4.72 μM for their target, Mycobacterium tuberculosis (Mt) ketol-acid reductoisomerase (KARI). In addition, these compounds have excellent in vitro activity against Mt H37Rv with MIC values as low as 1 μM. The mode of binding for these compounds to Mt KARI was investigated through molecular docking and dynamics simulations. Furthermore, these compounds were evaluated for their activity in Mt infected macrophages, and showed inhibitory activities with up to a 1.9-fold reduction in growth (at 10 μM concentration). They also inhibited Mt growth in a nutrient starved model by up to 2.5-fold. In addition, these compounds exhibited low toxicity against HEK 293T cell lines. Thus, these compounds are promising Mt KARI inhibitors that can be further optimized into anti-tuberculosis agents

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17*

Methylation of the arginine residues of histones by methyltransferases has important consequences for chromatin structure and gene regulation; however, the molecular mechanism(s) of methyltransferase regulation is still unclear, as is the biological significance of methylation at particular arginine residues. Here, we report a novel specific inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1; also known as PRMT4) that selectively inhibits methylation at arginine 17 of histone H3 (H3R17). Remarkably, this plant-derived inhibitor, called TBBD (ellagic acid), binds to the substrate (histone) preferentially at the signature motif, “KAPRK,” where the proline residue (Pro-16) plays a critical role for interaction and subsequent enzyme inhibition. In a promoter-specific context, inhibition of H3R17 methylation represses expression of p21, a p53-responsive gene, thus implicating a possible role for H3 Arg-17 methylation in tumor suppressor function. These data establish TBBD as a novel specific inhibitor of arginine methylation and demonstrate substrate sequence-directed inhibition of enzyme activity by a small molecule and its physiological consequence