Anti-cholinesterase hybrids as multi-target-directed ligands against Alzheimer’s disease (1998–2018)

Alzheimer’s disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.     

食药用真菌多糖对肿瘤免疫逃逸调节作用机制研究进展

食药用真菌多糖是食药用真菌的主要天然生物活性成分,可以从多层次、多靶点调节机体的免疫功能,被认为是一种天然免疫调节剂。此前食药用真菌多糖抗肿瘤机制研究集中在提升机体的免疫力达到抑制肿瘤的目的,但近年的研究表明它可以调节肿瘤微环境,恢复机体对肿瘤以及肿瘤微环境的监视能力,提升机体对肿瘤微环境的特异性免疫应答能力,进而达到充分发挥其抑制和杀伤肿瘤的功能。我们课题组前期研究中也发现食药用菌多糖可以正向调节肿瘤小鼠外周血免疫细胞数量,促进免疫细胞浸润到肿瘤微环境中帮助机体识别及杀伤肿瘤细胞,改善肿瘤微环境免疫状态。本文在我们团队的研究工作的基础上,结合国内外文献总结食药用真菌多糖作为免疫调节剂在抑制肿瘤免疫逃逸中的生物活性,结合肿瘤微环境探讨其与肿瘤免疫的关系、作用机制和在肿瘤治疗中的作用,以期为食药用真菌多糖免疫治疗提供新思路。     

Recent synthesis of aminophosphonic acids as potential biological importance

Aminophosphonic acids are an important group of medicinal compounds, and their synthesis has been a focus of considerable attention in synthetic organic chemistry as well as medicinal chemistry. Although the phosphonic and carboxylic acid groups differ considerably with respect to shape, size, and acidity, α-aminophosphonic acids are considered to be structural analogues of the corresponding amino acids and the transition state mimics peptide hydrolysis. This review summarizes recent developments in the synthesis, characterization and biological activity of α-aminophosphonic acid and N-analogues. An account of both uses will be presented, emphasizing one of the potential future developments, and some implications in medicinal chemistry are also disclosed. In addition, a brief account on the characterization of N-(phosphonomethyl) glycine derivatives will be presented.     

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using ‘click’ chemistry with copper- or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the ‘linker’ property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective agents. The present review summarises advances in lead compounds of 1,2,3-triazole-containing hybrids, conjugates, and their related heterocycles in medicinal chemistry published in 2018. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.     

Halogenase engineering and its utility in medicinal chemistry

Halogenation is commonly used in medicinal chemistry to improve the potency of pharmaceutical leads. While synthetic methods for halogenation present selectivity and reactivity challenges, halogenases have evolved over time to perform selective reactions under benign conditions. The optimization of halogenation biocatalysts has utilized enzyme evolution and structure-based engineering alongside biotransformation in a variety of systems to generate stable site-selective variants. The recent improvements in halogenase-catalyzed reactions has demonstrated the utility of these biocatalysts for industrial purposes, and their ability to achieve a broad substrate scope implies a synthetic tractability with increasing relevance in medicinal chemistry.     

天然药物化学实验教学改革与思考

天然药物化学是药学专业一门重要的专业基础课程。近年来,天然药物在世界范围内受到广为重视与青睐,而随着国家中医药现代化步伐的加快,对创新型药学专业人才的培养也提出了迫切的要求,天然药物化学实验在教学中的重要性与日俱增。为了进一步提高天然药物化学实验课程的教学效果,使之紧密切合学科发展的前沿,笔者根据本教研室在实验教学实践中的相关经验,结合该课程的特点与定位,总结了天然药物化学实验教学过程中存在的问题,并对课程改革进行了探讨与思考,针对课程重视程度低、教学中环保和可持续发展理念缺失、教学方法和手段单一、实验评价考核体系不合理等问题,提出了完善课程设计、严密教学方案、改进课程内容、改革考核标准等具体改进方法及措施。     

Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application

Curcumin is an admired, plant‐derived compound that has been extensively investigated for diverse range of biological activities, but the use of this polyphenol is limited due to its instability. Chemical modifications in curcumin are reported to seize this limitation; such efforts are intensively performed to discover molecules with similar but improved stability and better properties. Focal points of these reviews are synthesis of stable pyrazole and isoxazole analogs of curcumin and application in various biological systems. This review aims to emphasize the latest evidence of curcumin pyrazole analogs as a privileged scaffold in medicinal chemistry. Manifold features of curcumin pyrazole analogs will be summarized herein, including the synthesis of novel curcumin pyrazole analogs and the evaluation of their biological properties. This review is expected to be a complete, trustworthy and critical review of the curcumin pyrazole analogs template to the medicinal chemistry community.     

Medicinal chemistry and therapeutic potential of CpG DNA

The observation that oligodeoxynucleotides containing CpG dinucleotides (CpG DNA) exhibit several immunological effects has led to their use as therapeutic agents and adjuvants for various diseases. Several CpG DNA drug candidates are currently being evaluated, either as monotherapies or as adjuvants (with vaccines, antibodies, antigens and allergens), in preclinical and clinical trials against cancers, viral and bacterial infections, allergies and asthma. Knowledge gained from studies of the medicinal chemistry of CpG DNA has provided a basis for designing a second generation of CpG DNA agents with desirable cytokine-inducing and potent immunomodulatory activity. This article reviews recent progress in understanding the effects of CpG DNA, the medicinal chemistry of CpG DNA, and its possible therapeutic applications.     

Nonpeptidic ligands for peptide and protein receptors.

The first potent nonpeptidic ligands for somatostatin, luteinizing hormone-releasing hormone, glucagon and bradykinin receptors have been reported. Nonpeptidic clinical candidates have been identified or are currently under study for substance P, bradykinin, endothelin, growth hormone secretagogue, angiotensin, vasopressin, motilin and cholecystokinin. Design, screening, combinatorial chemistry and classical medicinal chemistry all played important roles in these advances.     

Identification of chemically diverse Chk1 inhibitors by receptor-based virtual screening

Inhibition of the Chk1 kinase by small molecules is of great therapeutic interest for oncology and in understanding the cellular regulation of the G2/M checkpoint. We report how computational docking of a large electronic catalogue of compounds to an X-ray structure of the Chk1 ATP-binding site allowed prioritisation of a small subset of these compounds for assay. This led to the discovery of 10 novel Chk1 inhibitors, distributed among nine new and clearly different chemical scaffolds. Several of these scaffolds have promising lead-like properties. All these ligands act by competitive binding to the targeted ATP site. The crystal structures of four of these compounds bound to this site are presented, and reasonable modelled docking modes are suggested for the 5 other scaffolds. This structural context is used to assess the potential of these scaffolds for further medicinal chemistry efforts, suggesting that several of them could be elaborated to make additional interactions with the buried part of the ATP site. Some unusual interactions with the conserved kinase backbone motif are pointed out. The ligand-binding modes are also used to discuss their medicinal chemistry potential with respect to undesirable chemical functionalities, whether these functionalities bind directly to the protein or not. Overall, this work illustrates how virtual screening can identify a diverse set of ligands which bind to the targeted site. The structural models for these ligands in the Chk1 ATP-binding site will facilitate further medicinal chemistry efforts targeting this kinase.     

An exhaustive compilation on chemistry of triazolopyrimidine: A journey through decades

The triazolopyrimidine scaffold represents one of the privileged structure in chemistry, and there has been an increase in number of studies utilizing this scaffold and its derivatives. Optimization of synthetic protocols such as aza-Wittig reaction, [3 + 2] cycloaddition reaction along with previous methods including condensation with 1,3-dicarbonyl substrates and oxidation of aminopyrimidine Schiff bases have been performed to obtain desired triazolopyrimidines. The triazolopyrimidine ring has been extensively used as a template in medicinal chemistry for its diverse pharmacological properties. Several medicinally active molecules possessing triazolopyrimidine scaffold, either fused or coupled with other heterocycles, have been reported in the literature, highlighting the significance of this nucleus. Interestingly, the unique triazolopyrimidine scaffold also exhibits an impressive potential as a ligand for the synthesis of several metal complexes with significant biological potential. Literature provides enough evidence of exhaustive exploration of this scaffold as a ligand for the chelates of platinum, ruthenium and other metals. This review aims to be a comprehensive and general summary of the different triazolopyrimidine syntheses, their use as ligands for the synthesis and development of metal complexes as medicinal agents and their main biological activities.     

5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods

5-Substituted-1H-tetrazoles (RCN4H) are often used as metabolism-resistant isosteric replacements for carboxylic acids (RCO2H) in SAR-driven medicinal chemistry analogue syntheses. This review provides a brief summary of the medicinal chemistry of tetrazolic acids and highlights some examples of tetrazole-containing drug substances in the current literature. A survey of representative literature procedures for the preparation of 5-substituted-1H-tetrazoles, focusing on preparations from aryl and alkyl nitriles, is presented in sections by generalized synthetic methods.     

Improving success rates for lead generation using affinity binding technologies

Affinity technologies have been applied at several stages of the drug discovery process, ranging from target identification and purification to the identification of preclinical candidates. The detection of ligand-macromolecule interactions in lead discovery is the best studied and most powerful of these techniques. Although affinity methods have been in widespread use for about a decade, only recently have many reports emerged on their utility. Primary affinity screens of large libraries of small molecules or fragments have begun to produce results for challenging targets. Furthermore, in secondary assays affinity methods are opening new avenues to tackle important medicinal chemistry tasks.     

天然药物化学实验教学模式的改革探索

天然药物化学是药学专业一门重要的必修课程。其实验课以培养学生的综合实验技能,提高学生的创新能力为主。针对天然药物化学实验教学中存在的问题,对其实验教学内容和方法作出相应的改革,以提高教学效果和质量。     

Can we rationally design promiscuous drugs?

Structure-based drug design is now used widely in modern medicinal chemistry. The application of structural biology to medicinal chemistry has heralded the "rational drug design" vision of discovering exquisitely selective ligands. However, recent advances in post-genomic biology are indicating that polypharmacology may be a necessary trait for the efficacy of many drugs, therefore questioning the "one drug, one target" assumption of current rational drug design. By combining advances in chemoinformatics and structural biology, it might be possible to rationally design the next generation of promiscuous drugs with polypharmacology.     

Advances in antihypertensive therapy: Non-peptide angiotensin II receptor antagonists as potent therapeutic agents

Summary The development of drugs that selectively block angiotensin receptors has resulted largely from a process of trialand-error medicinal chemistry on an early lead. The new generation of angiotensin antagonists or angiotensin mimetics are essentially devoid of side effects and are set to replace the angiotensin converting enzyme inhibitors for the treatment of cardiovascular diseases.     

Rational approaches,design strategies,structure activity relationship and mechanistic insights for therapeutic coumarin hybrids

Hybrid molecules, furnished by combining two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery that has attracted substantial traction in the past few years. Naturally occurring scaffolds such as coumarins display a wide spectrum of pharmacological activities including anticancer, antibiotic, antidiabetic and others, by acting on multiple targets. In this view, various coumarin-based hybrids possessing diverse medicinal attributes were synthesized in the last five years by conjugating coumarin moiety with other therapeutic pharmacophores. The current review summarizes the recent development (2014 and onwards) of these pharmacologically active coumarin hybrids and demonstrates rationale behind their design, structure-activity relationships (SAR) and mechanistic studies performed on these hybrid molecules. This review will be beneficial for medicinal chemist and chemical biologist, and in general to the drug discovery community and will facilitate the synthesis and development of novel, potent coumarin hybrid molecules serving as lead molecules for the treatment of complex disorders.     

Exploring structure-promiscuity relationships using dual-site promiscuity cliffs and corresponding single-site analogs

Currently available volumes of compounds and biological activity data enable large-scale analyses of compound promiscuity (multi-target activity). To aid in the exploration of structure-promiscuity relationships, promiscuity cliffs (PCs) were introduced previously. In analogy to activity cliffs, PCs were defined as pairs of structurally analogous compounds with large differences in the number of targets they are active against. Hence, PCs reveal small chemical modifications that are implicated in promiscuity. As introduced originally, PCs were identified by applying the matched molecular pair formalism and were thus confined to changes at a single substitution site. Herein, PCs with multiple substitution sites are introduced and a pilot study on a large collection of protein kinase inhibitors is reported, which provide excellent test cases for promiscuity analysis. For dual-site PCs (dsPCs), which dominated the distribution of multi-site PCs, an extended data structure was generated comprising a dsPC and two single-site analogs accounting for individual substitutions. Using a canonical representation, extended dsPCs are intuitive and easy to interpret from a chemical perspective. The analog quartet representing an extended dsPC is rich in structure-promiscuity relationship information and makes it possible to evaluate the potential interplay of chemical modifications implicated in promiscuity. Furthermore, extended dsPCs provide insights into possible experimental causes of apparent differences in analog promiscuity such as varying test frequencies. Hence, the newly introduced PC format should be of interest for exploring origins of compound promiscuity in medicinal chemistry and for formulating experimentally testable target hypotheses for analogs.