We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration.

Visual disability in this population was common, highly correctable, and frequently uncorrected. The impact of refractive error on self-reported visual function was significant. Strategies and studies to understand and remove barriers to spectacle wear are needed.

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This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016 , 59 , 7991 - 8007 ). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound 25a was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure-activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that 25a is a promising new drug candidate for treatment of HIV-1 infection.

Much attention has been addressed to the question of whether Europe or the UnitedStates adopts a more precautionary stance to the regulation of potential environmental, health, and safety risks. Some commentators suggest that Europe is more risk-averse and precautionary, whereas the US is seen as more risk-taking and optimistic about the prospects for new technology. Others suggest that the US is more precautionary because its regulatory process is more legalistic and adversarial, while Europe is more lax and corporatist in its regulations. The flip-flop hypothesis claims that the US was more precautionary than Europe in the 1970s and early 1980s, and that Europe has become more precautionary since then. We examine the levels and trends in regulation of environmental, health, and safety risks since 1970. Unlike previous research, which has studied only a small set of prominent cases selected non-randomly, we develop a comprehensive list of almost 3,000 risks and code the relative stringency of regulation in Europe and the US for each of 100 risks randomly selected from that list for each year from 1970 through 2004.Our results suggest that: (a) averaging over risks, there is no significant difference in relative precaution over the period, (b) weakly consistent with the flip-flop hypothesis, there is some evidence of a modest shift toward greater relative precaution of European regulation since about 1990, although (c) there is a diversity of trends across risks, of which the most common is no change in relative precaution (including cases where Europe and the US are equally precautionary and where Europe or the US has been consistently more precautionary). The overall finding is of a mixed and diverse pattern of relative transatlantic precaution over the period.

To assess and improve the accuracy of lay screeners compared with vision professionals in detecting visual impairment in secondary schoolchildren in rural China. Methods: After brief training, 32 teachers and a team of vision professionals independently measured vision in 1892 children in Xichang. The children also underwent vision measurement by health technicians in a concurrent government screening program. Results: Of 32 teachers, 28 (87.5%) believed that teacher screening was worthwhile. Sensitivity (93.5%) and specificity (91.2%) of teachers detecting uncorrected presenting visual acuity of 20/40 or less were better than for presenting visual acuity (sensitivity, 85.2%; specificity, 84.8%). Failure of teachers to identify children owning

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A novel series of diarylpyrimidine derivatives, which could simultaneously occupy the classical NNRTIs binding pocket (NNIBP) and the newly reported "NNRTI Adjacent" binding site, were designed, synthesized, and evaluated for their antiviral activities in MT-4 cell cultures. The results demonstrated that six compounds (, and-) showed excellent activities against wild-type (WT) HIV-1 strain (EC = 2.4-3.8 nM), which were more potent than that of ETV (EC = 4.0 nM). Furthermore, ,, , and showed more potent or equipotent activity against single mutant HIV-1 strains compared to that of ETV. Especially, showed marked antiviral activity, which was 1.5-fold greater against WT and 1.5- to 3-fold greater against L100I, K103N, Y181C, Y188L, and E138K when compared with ETV. In addition, all compounds showed lower toxicity (CC = 5.1-149.2 μM) than ETV (CC = 2.2 μM). The HIV-1 RT inhibitory assay was further conducted to confirm their binding target. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed comprehensively.