Design,synthesis, and biological evaluation of 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif inhibitors

Viral infectivity factor (Vif) is one of the accessory protein of human immunodeficiency virus type I (HIV-1) that inhibits host defense factor, APOBEC3G (A3G), mediated viral cDNA hypermutations. Previous work developed a novel Vif inhibitor 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide (1) with strong antiviral activity. Through optimizations on the two side branches, a series of compound 1 derivatives (2–18) were designed, synthesized and tested in vitro for their antiviral activities. The biological results showed that compound 5 and 16 inhibited the virus replication efficiently with EC₅₀ values of 9.81 and 4.62 μM. Meanwhile, low cytotoxicities on H9 cells were observed for the generated compounds by the MTT assay. The structure–activity relationship of compound 1 was preliminarily clarified, which gave rise to the development of more potent Vif inhibitors.     

Structure-activity relationships study of neolamellarin A and its analogues as hypoxia inducible factor-1 (HIF-1) inhibitors

The novel marine pyrrole alkaloid neolamellarin A derived from sponge has been shown to inhibit hypoxia-induced HIF-1 activity. In this work, we designed and synthesized neolamellarin A and its series of derivatives by a convergent synthetic strategy. The HIF-1 inhibitory activity and cytotoxicity of these compounds were evaluated in Hela cells by dual-luciferase reporter gene assay and MTT assay, respectively. The results showed that neolamellarin A 1 (IC₅₀ = 10.8 ± 1.0 μM) and derivative 2b (IC₅₀ = 11.9 ± 3.6 μM) had the best HIF-1 inhibitory activity and low cytotoxicity. Our SAR research focused on the effects of key regions aliphatic carbon chain length, aromatic ring substituents and C-7 substituent on biological activity, providing a basis for the subsequent research on the development of novel pyrrole alkaloids as HIF-1 inhibitors and design of small molecule probes for target protein identification.     

Design,synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure

Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC₅₀?=?3?nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.     

SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel,CNS penetrant tricyclic M4 PAMs

This letter describes progress towards an M₄ PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M₄ PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.     

Recent advances in natural antifungal flavonoids and their derivatives

The resistance of pathogenic fungi and failure of drug therapy increased dramatically. Numerous studies have reported the individual or synergistic antifungal potency of natural and synthesized flavonoids, especially against drug-resistant fungi. This brief review summarizes the structure and individual or synergistic antifungal activity of natural and synthesized flavonoids (literatures mainly cover the past 10 years 2009–2019), with a special focus on the antifungal spectra, structure–activity relationship and mechanisms of actions. These may contribute to a better understanding of flavonoids as multi-target agents in the treatment of mycoses and provide some ideas on the development of novel flavonoids-based antifungals.     

Structure-activity relationships of trichothecenes against COLO201 cells and Cochliobolus miyabeanus: The role of 12-epoxide and macrocyclic moieties

The novel trichothecene 12-deoxytrichodermin (3) was isolated from the fungus Trichoderma sp. 1212-03, and included with other known natural trichothecenes in a structure-activity relationship investigation against a human colon cancer cell line (COLO201) and filamentous fungus Cochliobolus miyabeanus. This revealed that the 12-epoxide functionality is critical for the cytotoxicity of simple trichothecenes trichodermin (4) and deoxynivalenol (2), while not critical for the cytotoxicity of roridin J (6) and epiisororidin E (8). In contrast, 12-epoxide is essential for the antifungal activity.     

南昌市城镇空间扩展与景观生态风险的耦合关系

为探究城镇用地空间扩展对景观生态风险的影响,以南昌市为例,运用遥感、GIS及数理统计的方法,借助城镇扩展强度指数研究了南昌市2000—2017年城镇空间扩展的时空变化特征,构建了景观生态风险指数,以3 km×3 km的单元网格进行系统采样,探究城镇扩展下南昌市景观格局的动态变化和景观生态风险,最后基于地理加权回归(GWR)模型,定量分析2000—2017年南昌市城镇空间扩展与景观生态风险之间的耦合关系。结果表明:(1)2000—2017年,南昌市城镇用地增加了247.56 km~2,年均扩展速率达17.75 km~2,其中2000—2005年扩展最快,呈现出剧烈扩展的态势,扩展强度达到0.55。城镇扩展主要沿正北和西北方向扩展,分布在青山湖区、南昌县、新建区等,总体上呈快速扩展趋势;(2)南昌市景观格局以耕地为主,建设用地快速扩张,耕地、林地、草地面积持续减少,土地利用的景观格局指数反映此期间人类活动的干扰程度加剧,景观斑块数量增加,整体破碎度提高。借助地统计分析方法,计算得到南昌市景观生态风险由2000年的0.1354上升至2017年的0.1420,景观生态风险呈逐渐升高的趋势;(3)2000—2017年,城镇用地面积与景观生态风险、城镇空间扩展强度指数和景观生态险变化值之间,都呈现负相关影响,后者相关性在减弱。回归系数的空间分布上,由中部向外逐渐升高,低值位于城镇扩展较快的南昌市区,城镇的快速扩展使城镇用面积大幅增加,景观破碎度、损失度降低,景观生态风险随之降低;高值出现在进贤县、安义县等经济发展缓慢的地区,城镇用地扩展幅度小,扩展边界斑块破碎度大,分离度上升,景观生态风险增加。研究结果为促进城市建设与生态环境保护的相互协调,正确评价人类活动对城市生态系统的影响,以及南昌市的可持续发展和科学管理提供借鉴。     

Design,Synthesis and in Vitro Tumor Cytotoxicity Evaluation of 3,5‐Diamino‐N‐substituted Benzamide Derivatives as Novel GSK‐3β Small Molecule Inhibitors

Glycogen synthase kinase‐3 (GSK‐3) plays an important regulatory role in various signaling pathways; such as PI3 K/AKT, which is closely related to the occurrence and development of tumors. At present, the most reported active GSK‐3 inhibitors have the same structure: lactam ring or amide structure. To find out the GSK‐3β small molecule inhibitor with novel, safe, efficient and more uncomplicated synthesis method, we analyzed in‐depth reported crystal‐binding patterns of GSK‐3β small molecule inhibitor with GSK‐3β protein, and designed and synthesized 17 non‐reported 3,5‐diamino‐N‐substituted benzamide compounds. Their structures were confirmed by ¹H‐NMR, ¹³C‐NMR, and HR‐MS. The preliminary screening of tumor cytotoxicity of compounds in vitro was detected by MTT, and their structure–activity relationships were illustrated. The results have shown that 3,5‐diamino‐N‐[3‐(trifluoromethyl)phenyl]benzamide ( 4d ) exhibited significant tumor cytotoxicity against human colon cancer cells (HCT‐116) with IC₅₀ of 8.3 μm and showed commendable selectivity to GSK‐3β. In addition, Compound 4d induced apoptosis to some extent and possessed modest PK properties.