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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

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

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

Thermo-Mechanical Calculation of Printed Circuit Heat exchanger Using Homogenization

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Journal of Thermal Science 2022年第6期31卷 2309-2328页

作者： GARNIeR christophe.VINCeNT Sébastien LAMAGNeRe Pierre LeJeAIL Yves CACHON Lionel CeA DESIRESNENuclear Technology DepartmentCadarache F-13108 Saint-Paul-Lez-DuranceFrance

The Finite-element Method(FeM) is mainly used to design Compact Heat exchanger structures. However, the narrow channel structures require fine mesh to accurately compute stress and strain. Combined with the dimensions of the overall component, this leads to an excessively large numerical model and therefore long computing time. This is especially true for transient thermal analyses, which require taking into account the full geometry. It is therefore interesting to reduce the size of the mesh. Periodic homogenization is an efficient method for achieving this goal. It can be applied to the core of the structure when periodic patterns(identified on basis of the arrangement of the channels) exist. A method based on this technique, with some improvements, is proposed in this paper for thermal loading without internal pressure. In addition to the equivalent Homogenous Medium(eHM) replacing the periodic patterns, some explicit channels are interposed between the eHM and the cover plates. This has two advantages. The first is to smooth the transition of stiffness between the cover plates and the homogenized medium. The second one is to be able to directly compute stress and strain on the most critical channels located in this area. This paper assesses the method’s effectiveness for thermal loadings in order to conduct thermal stress analyses. First, the equivalent elastic constants of the eHM are obtained with a numerical Finite elements Method. Then, two 2D cases using eHM are compared against a 2D explicit model(i.e. explicit geometry for the core channels). These cases are chosen to validate the eHM itself and its effectiveness for a real section of the heat exchanger. Results show very good agreement with a relative difference lower than 1%. In addition, the sensitivity to the number of layers added between the eHM and the cover plates is analysed. It is recommended interposing at least two layers of patterns to obtain converged results for the considered configuration

关键词： compact heat exchanger thermal stress finite element method homogenization

3D models of dilated cardiomyopathy:Shaping the chemical,physical and topographical properties of biomaterials to mimic the cardiac extracellular matrix

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Bioactive Materials 2022年第1期7卷 275-291页

作者： Marie Camman Pierre Joanne Onnik Agbulut christophe.Helary Sorbonne Universit´e CNRSUMR 7574Laboratoire de Chimie de la Matiere Condensee de Paris4 place Jussieu(case 174)F-75005ParisFrance Sorbonne Universite Institut de Biologie Paris-Seine(IBPS)CNRS UMR 8256Inserm ERL U1164Biological Adaptation and Ageing7 quai St-Bernard(case 256)F-75005ParisFrance

The pathophysiology of dilated cardiomyopathy(DCM),one major cause of heart failure,is characterized by the dilation of the heart but remains poorly understood because of the lack of adequate in vitro *** 2D models do not allow for the 3D organotypic organization of cardiomyocytes and do not reproduce the eCM *** this review,the different strategies to mimic the chemical,physical and topographical properties of the cardiac tissue affected by DCM are *** advantages and drawbacks of techniques generating anisotropy required for the cardiomyocytes alignment are *** addition,the different methods creating macroporosity and favoring organotypic organization are ***,the advances in the induced pluripotent stem cells technology to generate cardiac cells from healthy or DCM patients will be *** to the biomaterial design,some features of the DCM extracellular matrix such as stiffness,porosity,topography or chemical changes can impact the cardiomyocytes function in vitro and increase their *** mimicking the affected heart,both at the cellular and at the tissue level,3D models will enable a better understanding of the pathology and favor the discovery of novel therapies.

关键词： Biomaterials Dilated cardiomyopathies Induced pluripotent stem cells Porosity Anisotropy

Copper-uptake mediated by an ecofriendly zwitterionic ionic liquid: A new challenge for a cleaner bioeconomy

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Journal of environmental Sciences 2023年第8期130卷 92-101页

作者： Marie e.Vuillemin christophe.Waterlot Anthony Verdin Sylvain Laclef Christine Cézard David Lesur Catherine Sarazin Dominique Courcot Caroline Hadad eric Husson Albert Nguyen Van Nhien enzyme and Cell engineering UMR 7025 CNRSUniversity of Picardie Jules Verne-Faculty of Sciences33 rue Saint Leu80039 Amiens CedexFrance University of Lille Mines-Télécom InstituteUniversity of ArtoisJUNIAULR 4515-LGCgELaboratory of Civil Engineering and Geo-EnvironmentF-59000 LilleFrance environmental Chemistry and Life Interactions Unit UCEIV UR4492FR CNRS 3417University of Littoral Cote d’Opale(ULCO)DunkerqueFrance Laboratory of Glycochemistry Antimicrobials and AgroresourcesUMR CNRS 7378University of Picardie Jules Verne-Faculty of Sciences33 rue Saint Leu80039 Amiens CedexFrance Institute of Chemistry of Picardie FR CNRS 3085 80039 AmiensFrance

This study aims to investigate the ability of an imidazolium biobased Zwitterionic Ionic Liquids(ZILs)in enhancing the phytoavailability of copper from garden(G)and vineyard(V)soils using the model plant *** and artificially contaminated CuSO_(4) soils,unamended and ZIL-amended soil modalities were *** copper/ZIL molar ratio(1/4)introduced was rationally established based on molecular modeling and on the maximal copper concentration in artificially contaminated *** accumulation of copper in the shoots was detected for the uncontaminated and copper contaminated ZIL amended V soils(18.9 and 23.3 mg/kg,respectively)contrary to G soils together with a ZIL concentration of around 3%(W/W)detected by LC-MS *** data evidenced a Cu-accumulation improvement of 38%and 66%compared to non-amended V soils(13.6 and 13.9 mg/kg respectively).ZIL would be mainly present under Cu(II)-ZIL_(4) complexes in the *** impact on the chemical composition of shoot was also *** results show that depending on the soils modalitity,the presence of free copper and/or ZIL led to different chemical compositions in lignin and monomeric sugar *** the biorefinery context,performances of enzymatic hydrolysis of shoots were also related to the presence of both ZIL and copper under free or complex *** assessment of the vineyard soil samples indicated that the quantity of copper and ZIL remaining in the soils had no significant *** amendment in a copper-contaminated soil was demonstrated as being a promising way to promote the valorization of phytoremediation plants.

关键词： Cu-accumulation Biobased Zwitterionic Ionic Liquid (ZIL) enzymatic hydrolysis ecotoxicity

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

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

Recent development in metal halide perovskites synthesis to improve their charge-carrier mobility and photocatalytic efficiency

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Science China Materials 2023年第7期66卷 2545-2572页

作者： Marija Knezevic Thi-Hieu Hoang Nusrat Rashid Mojtaba Abdi-Jalebi christophe.Colbeau-Justin Mohamed Nawfal Ghazzal Universite Paris-Saclay Institut de Chimie PhysiqueUMR 8000 CNRS91405OrsayFrance Institute for Materials Discovery University College LondonMalet PlaceLondonWC1E 7JEUK

Over the past decade,all-inorganic metal halide perovskites(MHPs,CsPbX_(3):X=Cl,Br,I)have been widely investigated as promising materials for optoelectronic devices such as solar cells and light-emitting *** are defecttolerant,which allows tuning of their bandgap without altering their photophysical *** a fundamental point of view,MHPs are excellent candidates for photocatalytic reactions due to their light-harvesting capability,high photogenerated charge-carrier mobility,long diffusion lengths,and tunable bandgap *** this review,we provide an overview of various MHP engineering strategies(e.g.,surface,morphological,and structural modifications,heterojunction coupling,and encapsulation)which are directly linked to the charge-carrier mobility and lifetimes,and then to the photocatalytic ***,we outline different synthetic approaches resulting in surface and morphological modifications,anion/cation substitution,metallic doping,coupling,and encapsulation that tremendously influence MHPs’stability,optical properties,and charge-carrier dynamics at variable time scales(from fs toμs).We also provide an in-depth evaluation of the MHPs for variable photoredox reactions,discussing how the optical and electronic properties help to improve their stability and efficiency.

关键词： all-inorganic halide perovskite charge-carrier dynamics stability photocatalysis