Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Recent progress in reducing malaria cases and ensuing deaths is threatened by factors like mutations that induce resistance to artemisinin derivatives. Multiple drugs are currently in clinical trials for malaria treatment, including some with novel mechanisms of action. One of these, MMV390048, is a plasmodial kinase inhibitor. This review lists the recently developed molecules which target plasmodial kinases. A systematic review of the literature was performed using CAPLUS and MEDLINE databases from 2005 to 2020. It covers a total of 60 articles and describes about one hundred compounds targeting 22 plasmodial kinases. This work highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies. However, the majority of the Plasmodium kinome remains to be explored.     

Aryl-oxadiazole Schiff bases: Synthesis, α-glucosidase in vitro inhibitory activity and their in silico studies

α-Glucosidase enzyme is a therapeutic target for diabetes mellitus and its inhibitors play a vital role in the treatment of this disease. A new series of aryl-oxadiazole Schiff bases (1–18) were synthesized and evaluated for α-glucosidase inhibitory potential. Fifteen compounds 1–8, 11–13, and 15–18 showed excellent inhibition with IC₅₀ values ranging from 0.30 ± 0.2 to 35.1 ± 0.80 µM as compared to the standard inhibitor acarbose (IC₅₀ = 38.45 ± 0.80 µM), nonetheless, the remaining compounds were found to have moderate activity. Among the series, compounds 7 (IC₅₀ = 0.30 ± 0.2 μM) with hydroxy groups at phenyl rings on either side of the oxadiazole ring was identified as the most potent inhibitor of α-glucosidase. The molecular docking studies were conducted to understand the binding mode of active inhibitors with the active site of enzyme and results supported the experimental data.     

Synthesis,Antitumor Activity,and SAR of N-Substituted γ-Aminopropylsilatrane Derivatives

Abstract

γ-Aminopropylsilatrane has been reported to possess biological activity against tumor cancer cells with low cytotoxicity in many kinds of silatranes. So some N-substituted γ-aminopropylsilatrane derivatives were synthesized and assayed by a primary anticancer screening against HT-29, Hela, and MDAMB435 cells by the use of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The structures of these derivatives were confirmed by ¹H NMR, electrospray ionization-mass spectrometry, and elemental analysis. The structure–activity relationship showed that the N-substituted derivatives exhibit better activity in which the γ-amino group of the silatrane is connected with stronger electron-withdrawing groups.     

SAR—The U.S. Regulatory Perspective

Abstract

Structure-Activity Relationships (SAR) have been used for over a decade by the U.S. EPA's Office of Pollution Prevention and Toxics (OPPT) in their new chemicals program. The development and use of SAR resulted from the need to make rapid risk-based decisions on thousands of new chemicals per year while seldom receiving data on chemical properties, potential exposures, or hazards to humans or organisms in the environment. Qualitative SAR and quantitative SAR methods (QSAR) have been used to fill some of these data gaps by estimating the potential properties and hazards of such chemicals. SAR has been used to assess chemical hazards, identify testing needs, and set priorities. Validation of these SAR assessment tools is an ongoing process.     

The Application of Structure-Activity Relationships (SARs) in the Aquatic Toxicity Evaluation of Discrete Organic Chemicals

Abstract

The Office of Pollution Prevention and Toxics (OPPT), United States Environmental Protection Agency (USEPA) routinely uses structure-activity relationships (SAR) for the aquatic hazard assessment of new chemicals submitted under Section 5 of the Toxic Substances Control Act (TSCA). With 15 years of experience and the general acceptance of toxicity predictions based on SARs, OPPT has expanded the use and application of the methodology to include existing chemicals used in printing, dry cleaning, and paint stripping. SAR analysis has also been used in the hazard evaluation of the U.S. and EU/OECD high production volume (HPV) chemicals. This paper describes the assumptions, limitations, and methodology for the use of SARs to evaluate large sets of discrete organic chemicals.     

In silico exploratory study using structure–activity relationship models and metabolic information for prediction of mutagenicity based on the Ames test and rodent micronucleus assay

The mutagenic potential of chemicals is a cause of growing concern, due to the possible impact on human health. In this paper we have developed a knowledge-based approach, combining information from structure–activity relationship (SAR) and metabolic triggers generated from the metabolic fate of chemicals in biological systems for prediction of mutagenicity in vitro based on the Ames test and in vivo based on the rodent micronucleus assay. In the first part of the work, a model was developed, which comprises newly generated SAR rules and a set of metabolic triggers. These SAR rules and metabolic triggers were further externally validated to predict mutagenicity in vitro, with metabolic triggers being used only to predict mutagenicity of chemicals, which were predicted unknown, by SARpy. Hence, this model has a higher accuracy than the SAR model, with an accuracy of 89% for the training set and 75% for the external validation set. Subsequently, the results of the second part of this work enlist a set of metabolic triggers for prediction of mutagenicity in vivo, based on the rodent micronucleus assay. Finally, the results of the third part enlist a list of metabolic triggers to find similarities and differences in the mutagenic response of chemicals in vitro and in vivo.     

Integrated approach to assess the domain of applicability of some commercial (Q)SAR models1

An integrated framework of data analysis has been proposed to systematically address the determination of the domain of applicability (DA) of some commercial Quantitative Structure Activity Relationship ((Q)SAR) models based on the structure of test chemicals. This framework forms one of the important steps in dealing with the growing concerns on reliability of model-based predictions on toxicity of chemicals specifically in the regulatory context. The present study uses some of the well-known mutagenicity and carcinogenicity models that are available within the Casetox (MultiCASE Inc.) and TOPKAT (Accelrys Software Inc.) programs. The approach enumerated in this paper employs chemoinformatics tools that facilitate comparisons of key structural features as well as application of cluster analysis techniques. The approach has been illustrated using a set of eleven chemical structures selected from the Canadian Domestic Substances List (DSL) that are not present in the model training sets, and the efficacy of the approach has also been assessed using seven chemicals with known toxicities. The methodologies presented here could help address the issue of DA of complex (Q)SAR models and at the same time, serve as useful tools for regulators to make a preliminary assessment of (Q)SAR based systems thereby helping the process of hazard-based regulatory assessments of chemicals.     

基于小波的多极化机载合成孔径雷达海面风向反演

为了实现从合成孔径雷达(SAR)图像本身提取高精度的海面风向信息, 提高SAR海面风场反演精度,研究了多极化机载SAR海面风向反演技术, 借助小波分析相对傅里叶分析和局部梯度更精细的时-频分析能力, 将二维连续小波变换与快速傅里叶变换(FFT)相结合,提出一种新的机载SAR海面风向反演方法. 为验证反演方法的有效性,通过海上同步飞行试验获取多极化机载SAR数据及同步调查船实测风向数据,用于反演试验的数据比对.采用本文提出的方法, 利用多种小波基对机载C波段SAR的同极化和交叉极化数据进行风向反演, 将反演结果与美国国家环境预报中心再分析资料以及调查船实测风向进行比对. 结果表明,本文提出的基于小波分析的海面风向反演方法适用于机载SAR探测数据, 反演精度优于二维FFT法和局部梯度方法;小波基的选择对反演结果影响较大, Mexican-Hat小波基是机载SAR海面风向反演的最优小波基, 且同极化与交叉极化机载SAR数据均可用于海面风向的反演.     

Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones were designed,synthesized and evaluated for their antiviral activities in MT-4 cells.Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC_(50) values ranging from 7.55 μmol/L to 0.018 μmol/L.Among them,compound 5 c was identified as the most promising inhibitor against HIV-1 replication with an IC_(50)=0.018 μmol/L,CC_(50)=194 μmol/L,and SI=12791,which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV.In addition,5 c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02.The preliminary structure-activity relationship(SAR) and molecular modeling studies were also discussed,which provides some useful indications for guiding the further rational design of new S-DACO analogues.