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design and optimization of piperidinesubstituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3110-3124页

作者： Yanying Sun Zhenzhen Zhou Zhongling Shi Fabao Zhao Minghui Xie Zongji Zhuo erik de Clercq christophe.Pannecouqueb dongwei Kang Peng Zhan Xinyong Liu department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJinan 250012China Rega Institute for Medical Research Laboratory of Virology and ChemotherapyK.U.LeuvenLeuven B-3000Belgium China-Belgium Collaborative Research Center for Innovative Antiviral drugs of Shandong Province Jinan 250012China

HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIdS),but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors(NNRTIs).This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drugresistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(dAPY)derivatives were prepared via structural modifications of the leads K-5a2 and *** them,15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel,being 1.6-fold(WT,eC_(50) Z 1.75 nmol/L),3.0-fold(L100I,eC_(50) Z 2.84 nmol/L),2.4-fold(K103N,eC_(50) Z 1.27 nmol/L),3.3-fold(Y181C,eC50 Z 5.38 nmol/L),2.9-fold(Y188L,eC_(50) Z 7.96 nmol/L),2.5-fold(e138K,eC_(50) Z 4.28 nmol/L),4.8-fold(F227L/V106A,eC_(50) Z 3.76 nmol/L)and 5.3-fold(ReS056,eC_(50) Z 15.8 nmol/L)more effective than that of the marketed drug *** docking results illustrated the detailed interactions formed by compound 15a and WT,F227L/V106A,and ReS056 ***,15a-HCl carried outstanding pharmacokinetic(t1/2 Z 1.32 h,F Z 40.8%)and safety profiles(Ld_(50)>2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.

关键词： HIV-1 NNRTIs NNIBP Structural alert Anti-HIV-1 drug candidate

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Lateral ring compression test applied to a small caliber steel jacket:Identification of a constitutive model

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defence Technology（防务技术） 2024年第6期36卷 133-148页

作者： Yann Coget Yael demarty christophe.Czarnota Anthony Bracq Jean-Sebastien Brest Alexis Rusinek French-German Research Institute of Saint-Louis 5 Rue Du General Cassagnou68300 Saint-LouisFrance Laboratoire d'etude des Microstructures et de Mecanique des Materiaux(LeM3) CNRSUniversite de LorraineArts&Metiers ParisTechF-57000 MetzFrance

The evolution of threats and scenarios requires continuous performance improvements of ballistic protections for armed *** a modeling point of view,it is necessary to use sufficiently precise material behavior models to accurately describe the phenomena observed during the impact of a projectile on a protective *** this context,the goal of this paper is to characterize the behavior of a small caliber steel jacket by combining experimental and numerical *** experimental method is based on the lateral compression of ring specimens directly machined from the thin and small *** speeds and temperatures are considered in a quasi-static regime in order to reveal the strain rate and temperature dependencies of the tested *** Finite element Updating Method(FeMU)is *** results are coupled with an inverse optimization method and a finite element numerical model in order to determine the parameters of a constitutive model representative of the jacket *** of the present model are verified against experimental results and a parametric study as well as a discussion on the identified material parameters are *** results indicate that the strain hardening parameter can be neglected and the behavior of the thin steel jacket can be described by a modeling without strain hardening sensitivity.

关键词： Full metal jacket ammunition Lateral ring compression Inverse identification Numerical simulation

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Lighting up aggregate emission of perylene diimide by leveraging polymerization-mediated through-space charge transfer and π-π stacking

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Science China Chemistry 2024年

作者： Suiying Ye désirée Füglistaller Tian Tian Anjay Manian Sudhir Kumar Celine Nardo Andrew J.Christofferson Salvy P.Russo Chih-Jen Shih Jean-christophe.Leroux Yinyin Bao Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Zurich Vladimir-Prelog-Weg 3 Institute for Chemical and Bioengineering Department of Chemistry and Applied Biosciences ETH Zurich Vladimir-Prelog-Weg 1-5 ARC Centre of excellence in exciton Science School of Science RMIT University School of Science STEM College RMIT University

The molecular engineering of fluorescent organic/polymeric materials, specifically those emitting in the deep red to near-infrared spectrum, is vital for advancements in optoelectronics and biomedicine. Perylene diimide(PdI), a well-known fluorescent scaffold, offers high thermal and photophysical stability but suffers from fluorescence quenching in solid or aggregate states due to intense π-π interactions. To mitigate this, simple and versatile methods for strong PdI aggregate emission without extensive synthetic demands are highly desirable but still lacking. Here, we report a straightforward strategy to enhance the solid-state emission of PdI by introducing certain degree of through-space charge transfer(TSCT) via controlled radical polymerization,which can efficiently distort the typical face-to-face PdI stacking, enabling greatly enhanced deep red emission. This is achieved by growing electron-donating star-shape styrenic(co)polymers from a multidirectional electron-accepting PdI initiator. The incorporation of polycyclic aromatic monomers further shifted the emission into the near-infrared region, albeit with a reduced intensity. Overall, the emission of the PdI-based TSCT polymers can be systematically manipulated by leveraging the balance between PdI stacking and the TSCT degree, as confirmed by both experimental study and theoretical calculations. Our approach circumvents complex synthetic procedures, offering highly emissive materials with large Stokes shifts and showing broad potential for optoelectronic technology.

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Quantum-mechanical effects in photoluminescence from thin crystalline gold films

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Light(Science & Applications) 2024年第4期13卷 783-794页

作者： Alan R.Bowman Alvaro Rodríguez echarri Fatemeh Kiani Fadil Iyikanat Ted V.Tsoulos Joel d.Cox Ravishankar Sundararaman F.Javier García de Abajo Giulia Tagliabue Laboratory of Nanoscience for energy Technologies(LNeT) STIÉcole Polytechnique Fédérale de Lausanne(EPFL)LausanneSwitzerland ICFO–Institut de Ciencies Fotoniques The Barcelona Institute of Science and TechnologyCastelldefels(Barcelona)Spain. MBI–Max-Born-Institut BerlinGermany. POLIMA–Center for Polariton-driven Light–Matter Interactions University of Southern DenmarkOdense MDenmark. danish Institute for Advanced Study University of Southern DenmarkOdense MDenmark. department of Materials Science&engineering Rensselaer Polytechnic InstituteTroyNYUSA. department of Physics Applied Physicsand AstronomyRensselaer Polytechnic InstituteTroyNYUSA. ICReA–Institucio Catalana de Recerca i estudis Avancats BarcelonaSpain

Luminescence constitutes a unique source of insight into hot carrier processes in metals,including those in plasmonic nanostructures used for sensing and energy ***,being weak in nature,metal luminescence remains poorly understood,its microscopic origin strongly debated,and its potential for unraveling nanoscale carrier dynamics largely ***,we reveal quantum-mechanical effects in the luminescence emanating from thin monocrystalline gold ***,we present experimental evidence,supported by first-principles simulations,to demonstrate its photoluminescence origin(i.e.,radiative emission from electron/hole recombination)when exciting in the interband *** model allows us to identify changes to the measured gold luminescence due to quantum-mechanical effects as the gold film thickness is ***,such effects are observable in the luminescence signal from flakes up to 40 nm in thickness,associated with the out-of-plane discreteness of the electronic band structure near the Fermi *** qualitatively reproduce the observations with first-principles modeling,thus establishing a unified description of luminescence in gold monocrystalline flakes and enabling its widespread application as a probe of carrier dynamics and light-matter interactions in this *** study paves the way for future explorations of hot carriers and charge-transfer dynamics in a multitude of material systems.

关键词： luminescence quantum crystalline

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Co-Morbidities Associated with Prematurity in Two Referral Hospitals in Cameroon

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Open Journal of Pediatrics 2024年第4期14卷 738-753页

作者： diomede Noukeu Njinkui dominique enyama Yolande djike Fokam Cyrelle O. Mefotse Saha Beatrice Moudze Kaptue Charlotte eposse Koube Annick A. Tchouamo Sime christophe.Akazong Adjahoung Marthe e. Barla edgar Mandeng Ma Linwa Seraphin Nguefack Faculty of Medicine and Pharmaceutical Sciences of the University of dschang Dschang Cameroon Faculty of Health Sciences University of Buea Buea Cameroon Faculty of Health Sciences University of Mountains Bangangte Cameroon douala Laquintinie Hospital Douala Cameroon Faculty of Medicine and Pharmaceutical Sciences University of Douala Douala Cameroon douala General Hospital Douala Cameroon Faculty of Medicine and Biomedical Sciences University of Yaound I Yaound Cameroon

Introduction: Prematurity is the leading cause of neonatal death in Africa. More than a million children die each year due to co-morbidities related to prematurity. In addition to being one of the causes of neonatal deaths, the health problems associated with prematurity can also lead to severe lifelong impairment in those who survive. Objectives: This paper aims to determine the epidemiology and identify co-morbidities of prematurity in the neonatology units of the douala General Hospital (dGH) and the Laquintinie Hospital of douala (LHd). Patients and Methodology: We conducted an analytical retrospective cohort study from January 2015 to January 2018 in the neonatology department of the GdH and the LHd, which are considered reference hospitals for the management of preterm babies in Cameroon. We included all newborns aged less than 37 weeks admitted to the neonatology units of the GdH and the LHd. The descriptive component was based on the analysis of quantitative variables using measures of central tendency. The analytical component was evaluated using Spearman correlations and the Chi-square and Fisher tests. Simple and multiple logistic regressions measured factors predictive of mortality. The Kaplan Meier survival curve used the Log Rank test and significance at p ≤ 0.05. Results: We recorded 908 preterm newborns in neonatal service and 1,124 preterm deliveries in maternity, representing an incidence of 32.5% in neonatal unit and 10.6% in maternity. 51% of whom were girls, given a sex ratio M/F of 0.9. Hypertension was the main prenatal pathology (9.1%), while premature rupture of membranes: PROM (35.5%) and eclampsia/pre-eclampsia (18.6%) were the most common obstetrical pathologies. 75.9% of deliveries were vaginal with 65.2% being performed in our referral hospitals. Gestational age ranged from 22 to 36 weeks, with a mean of 32.4 weeks. Late preterm birth rate was 53.7%, and birth weight varied between 590 and 3200 g with an average of 1747 ± 479 g. The per

关键词： epidemiology Co-Morbidities Prematurity douala

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Linker optimization of HePT derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors: From S=O to CHOR

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Chinese Chemical Letters 2023年第4期34卷 188-192页

作者： Qingqing Hao Xu Ling christophe.Pannecouque erik de Clercq Fener Chen Sichuan Research Center for drug Precision Industrial Technology West China School of PharmacySichuan UniversityChengdu 610041China department of Chemistry Engineering Center of Catalysis and Synthesis for Chiral MoleculesFudan UniversityShanghai 200433China Shanghai engineering Center of Industrial Asymmetric Catalysis for Chiral drugs Shanghai 200433China Rega Institute for Medical Research KU LeuvenHerestraat 49Leuven B-3000Belgium

A novel series of CHOR-HePT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed by means of structure-based design strategy based on compound 6 reported previously by our group. Most of these compounds showed moderate to good activity toward wild-type HIV-1 strain with eC50values in the range of 0.18–51.88 μmol/L and SI values in the range of 4–907. The compound 14aj with a CHOH linker and compound 13i with a CHOTMS linker in this series exhibited improved anti-HIV-1 activity(eC50= 0.18 μmol/L, and 0.20 μmol/L) with higher selectivity(SI = 907, and 665) as comparison with the lead compound 6(eC50= 0.59 μmol/L, SI = 9). These two compounds 14aj and 13i were more sensitive than 6 toward clinically relevant mutant L100I, K103N and e138K viruses, which were further evaluated for their activity against wild-type reverse transcriptase and displayed a good correlation with the cell-based activity. Preliminary molecular modeling investigations provided insight for further structural optimization of HePT.

关键词： HIV NNRTIs HePTs RT Optimization

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Structure-based design of novel heterocyclesubstituted ATdP analogs as non-nucleoside reverse transcriptase inhibitors with improved selectivity and solubility

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4906-4917页

作者： Li-Min Zhao christophe.Pannecouque erik de Clerc Shuai Wang Fen-er Chen Key Laboratory of Natural Resources of Changbai Mountain&Functional Molecules Ministry of EducationYanbian University College of PharmacyYanbian UniversityYanji 133002China engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai engineering Center of Industrial Asymmetric Catalysis for Chiral drugs Shanghai 200433China Rega Institute for Medical Research KU LeuvenLeuven B-3000Belgium

Following on our recently developed biphenyl-ATdP non-nucleoside reverse transcriptase inhibitor ZLM-66(SI=2019.80,S=1.9μg/mL),a series of novel heterocycle-substituted ATdP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower ***,the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility(SI=12,497.73,S=4472μg/mL)in comparison with ZLM-66(SI=2019.80,S=1.9μg/mL).This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains(K103N,L1001,Y181C,e138K,and K103N+Y181C).The analog also demonstrated favorable safety and pharmacokinetic profiles,as evidenced by its insensitivity to CYP and heRG,lack of mortality and pathological damage,and good oral bioavailability in rats(F=27.1%).Further development of 7w for HIV therapy will be facilitated by this valuable information.

关键词： HIV-1 RT NNRTIS ATdP Pyridone

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Fragment-based discovery of sulfur-containing diarylbenzopyrimidines as novel nonnucleoside reverse transcriptase inhibitors

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Chinese Chemical Letters 2020年第3期31卷 764-768页

作者： Sheng Han Yuan Lei christophe.Pannecouque erik de Clercq Chunlin Zhuang Fener Chen engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai engineering Center of Industrial Asymmetric Catalysis for Chiral drugs Shanghai 200433China Sichuan Research Center for drug Precision Industrial Technology West China School of PharmacySichuan UniversityChengdu 610041China Institute of Pharmaceutical Science and Technology Zhejiang University of TechnologyHangzhou 310014China Rega Institute for Medical Research KU LeuvenHerestraat 49B-3000 LeuvenBelgium

Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed dABP 3 and further *** best compound 6 e with a sulfonyl scaffold displayed eC(50)values of 0.0356μmol/L against WT and 0.0228μmol/L against HIV K103 N mutant *** pronounced,it had a lower cytotoxicity(CC(50)=99.6μmol/L),higher selectivity index(SIWT=2799,SIK103 N=4375)and better calculated logarithm of the octanol-water partition coefficient(cLogP)than the lead compound *** docking and dynamics provided the binding modes of these compounds with reve rse transcriptase,explaining their ***,the new compounds could be candidates for anti-HIV drug discovery.

关键词： HIV-1 NNRTIs dAPY Sulfur-containing dABPs FBdd

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development of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors:Boosting the safety and metabolic stability

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1192-1203页

作者： Xin Jin Shuai Wang Limin Zhao Wenjuan Huang Yinxiang Zhang christophe.Pannecouque erik de Clercq Ge Meng Huri Piao Fener Chen engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai engineering Center of Industrial Asymmetric Catalysis for Chiral drugs Shanghai 200433China Key Laboratory of Natural Resources of Changbai Mountain&Functional Molecules Ministry of EducationCollege of PharmacyYanbian UniversityYanji 133002China Rega Institute for Medical Research KU LeuvenLeuven B-3000Belgium

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1(eC_(50)=1.0 nmol/L),but the poor metabolic stability in human liver microsomes(t_(1/2)=14.6 min)and insufficient selectivity(SI=2059)with high cytotoxicity(CC_(50)=2.08μmol/L)remained major issues associated with *** present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b,leading to the discovery of a novel series of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain(eC_(50)=1.8–349 nmol/L).The best compound 5t in this collection(eC_(50)=1.8 nmol/L,CC_(50)=117μmol/L)was 32-fold in selectivity(SI=66,443)compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains,such as L100I,K103N,e138K,and *** metabolic stability of 5t was also significantly improved(t_(1/2)=74.52 min),approximately 5-fold higher than JK-4b in human liver microsomes(t_(1/2)=14.6 min).Also,5t possessed good stability in both human and monkey *** significant in vitro inhibition effect toward CYP enzyme and heRG was *** single-dose acute toxicity test did not induce mice death or obvious pathological *** findings pave the way for further development of 5t as a drug candidate.

关键词： HIV-1 NNRTI dAPYs Safety Metabolic stability

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Classification of Sandstone-Related Uranium deposits

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Journal of earth Science 2022年第2期33卷 236-256页

作者： Michel Cuney Julien Mercadier christophe.Bonnetti Universitéde Lorraine GéoRessourcesCNRSCREGUNancy F54500France 2.State Key Laboratory of Nuclear Resources and EnvironmentEast China University of TechnologyNanchang 330013China

Sandstone type deposits are the most common type of uranium deposits in the world.A large variety of sub-types have been defined,based either on the morphology of the deposits(e.g.,tabular,roll front,etc),or on the sedimentological setting(e.g.,paleovalley,paleochannel,unconformity),or on tectonic or lithologic controls(e.g.,tectonolithologic,mafic dykes/sills),or still on a variety of others characteristics(phreatic oxidation type,interlayer permeable type,multi-element stratabound infiltrational,solution front limb deposit,humate type,etc.),reflecting the diversity of the characteristics of these deposits,but making it difficult to have a clear overview of these ***,uranium deposits occurring in the same sedimentological setting(e.g.,paleochannel),presenting similar morphologies(e.g.,tabular),may result from different genetic mechanisms and thus can be misleading for exploration *** aim of the present paper is to propose a new view on sandstone-related uranium deposits combining both genetic and descriptive *** dual view is indeed of primordial importance because all the critical characteristics of each deposit type,not limited to the morphology/geometry of the ore bodies and their relationships with depositional environments of the sandstone,have to be taken into account to propose a comprehensive classification of uranium *** this respect,several key ore-forming processes,like the physical-chemical characteristics of the mineralizing fluid,have to be used to integrate genetic aspects in the *** a succession of concentration steps,potentially temporally-disconnected,are involved in the genesis of some uranium mineralization,the classification here proposed will focus on the main mechanisms responsible for the formation and/or the location of ore *** objective of this paper is also to propose a robust and widely usable terminology to define and categorize sandstone uranium deposits,considering

关键词： sandstone uranium genetic classification redox control depositional environment fluids ore deposit geology

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