Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based ...on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro2H-(1,3)-benzoxazine-2,4′-piperidine derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues.
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•Spiro2H-(1,3)-benzoxazine-2,4′-piperidine hydroxamates were designed and prepared.•Selected compounds showed good microsomal stability and reduced hERG affinity.•Two examples showed low clearance and good oral bioavailability in vivo.•The good PK properties translated in significant antitumor activity in vivo.
Peyssonol A, a brominated natural product with documented anti-HIV-1 activity, was synthesized racemically along with 6 isomers and 15 truncated analogues and synthetic precursors. These compounds ...were screened in a cell-based assay against a recombinant HIV-1 strain to investigate structure–activity relationships. The results obtained suggest that both the aliphatic and aromatic domains of peyssonol A are responsible for its potency, while the stereochemical configuration of the substituents on the aliphatic domain, including their bromine atom, are largely irrelevant. Although none of the analogues tested were as potent as the parent natural product, several exhibited greater therapeutic indices due to reduced cytotoxicity, noting that nearly all compounds tested were measurably cytotoxic.
The preparation of natural product-like polyhydroxylated pyrrolidine and piperidine alkaloids using a combination of solid- and solution-phase organic synthesis is described. The key intermediates, ...enantiopure five- or six-membered tri-O-benzyl cyclic nitrones, were efficiently prepared on solid support from accessible chiral furanosides and pyranosides, respectively. The substituent diversity was achieved by a diastereoselective addition of a variety of Grignard reagents to the cyclic nitrones in solution-phase synthesis. All reaction steps and work-up procedures were modified to allow the use of automated equipment. A 36-membered demonstration library with three diversity elements (core, configuration, and substituent) was prepared in good yield and purity.
We have developed a solid phase synthesis route to 1,5-substituted pyrazole-4-carboxamides with three diversity points aimed at the discovery of new compounds as potential G-Protein coupled receptor ...(GPCR) ligands. The new chemistry involves acylation of a resin bound secondary amine with a β-ketoester via transamidation, conversion of the resulting β-ketoamide to the corresponding vinylogous amide, pyrazole formation upon reaction with a aryl hydrzine, and cleavage of the product from the resin. Using the reported methodology, we describe the syntheses of multiple arrays of pyrazoles that were used collectively to construct a library of more than 1000 analogues. Several members of this library displayed submicromolar antagonist activities at the cannabinoid subtype 1 (CB-1) receptor.
The development of heterocyclic derivatives has progressed considerably over the past few decades, and many new agents of synthetic and natural origin have been produced. Among heterocyclic ...compounds, thiazole is a unique five-membered heterocyclic motif characterized by nitrogen and sulfur atoms, which is widely used as an important core skeleton in a variety of pharmaceutically important compounds due to their diverse biological activities, such as antibacterial, antivirus, and antifungal. To the best of our knowledge, more than 90 thiazole-containing derivatives have been currently under clinical investigation, and some thiazole analogs have been approved to treat various diseases. As the potentially privileged scaffolds, thiazole derivatives can be further extensively explored to search for new drugs characterized by improved therapeutic efficacy and similar biological targets. This review aims to outline the applications and synthetic routes of some representative thiazole-containing drugs approved in the clinic, which may guide medicinal researchers to rationally design more effective thiazole-containing drug candidates.
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•Thiazole ring is widely used in many drugs to treat various diseases.•Recent advances in thiazole-containing drugs have been summarized.•The clinical applications and synthetic routes of 33 thiazole-containing drugs are highlighted.•Summary and prospect are briefly discussed to guide future design of thiazole-containing drugs.
The catalytic asymmetric synthesis of 3,3-disubstituted oxindoles, a big family of privileged scaffolds in natural products and drugs, is of current interest. Recently, the catalytic asymmetric ...functionalization of diazooxindoles emerges as a potentially general and flexible strategy for this purpose, with several notable examples coming out in 2013. In this digest, synthetic applications of diazooxindoles have been summarized and discussed, which might be helpful for readers to understand the special properties of this type of donor/acceptor cyclic diazo reagent and to develop new catalytic asymmetric reactions.
The catalytic asymmetric synthesis of 3,3-disubstituted oxindoles, a big family of privileged scaffolds in natural products and drugs, is of current interest. Recently, the catalytic asymmetric functionalization of diazooxindoles emerges as a potentially general and flexible strategy for this purpose, with several notable examples coming out in 2013. In this digest, synthetic applications of diazooxindoles have been summarized and discussed, which might be helpful for readers to understand the special properties of this type of donor/acceptor cyclic diazo reagent and to develop new catalytic asymmetric reactions.
Aporphine alkaloids embedded in 4H-dibenzode,gquinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of ...organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D1/2/5, serotonin 5-HT1A/2A/2C and 5-HT7, adrenergic α/β receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.
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•Aporphine is a privileged scaffold for the discovery of new CNS therapeutic agents.•Aporphines are widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS.•The diverse CNS activities and general synthetic routes of aporphines are highlighted.
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The use of privileged scaffolds in medicinal chemistry is an effective way to accelerate the drug discovery process, especially at the hit/lead optimization stage. ...2-Phenylcyclopropylmethylamine (PCPMA) is a less commonly used chemical scaffold in medicinal chemistry, but many PCPMA-containing compounds exert therapeutic effects for various diseases, in particular central nervous system (CNS) diseases such as depression, schizophrenia, sleep disorder, and Parkinson’s disease. The backbone of the PCPMA scaffold enables a unique structure of an amino group linked to a benzene ring through an alkyl linker, making it a useful template for the design of bioactive compounds especially for CNS drug targets including aminergic GPCRs and transporters. This review summarizes the medicinal chemistry studies of PCPMA-containing drugs and drug-like molecules, their mechanisms of action, and biological activities. We conclude that PCPMA is a unique and useful privileged scaffold for CNS drug design.
Recent preclinical studies have shown that activation of the serotonin 5-HT7 receptor has the potential to treat neurodevelopmental disorders such as Fragile X syndrome, a rare disease characterized ...by autistic features. With the aim to provide the scientific community with diversified drug-like 5-HT7 receptor-preferring agonists, we designed a set of new long-chain arylpiperazines by exploiting structural fragments present in clinically approved drugs or in preclinical candidates (privileged scaffolds). The new compounds were synthesized, tested for their affinity at 5-HT7 and 5-HT1A receptors, and screened for their in vitro stability to microsomal degradation and toxicity. Selected compounds were characterized as 5-HT7 receptor-preferring ligands, endowed with high metabolic stability and low toxicity. Compound 7g emerged as a drug-like 5-HT7 receptor-preferring agonist capable to rescue synaptic plasticity and attenuate stereotyped behavior in a mouse model of Fragile X syndrome.
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•5-HT7 receptor agonists have the potential to treat Fragile X syndrome.•21 new 5-HT7 receptor ligands were synthesized by exploiting privileged scaffolds.•7g displayed good pharmacokinetic properties and low in vitro toxicity.•7g is a 5-HT7 receptor-preferring agonist capable to rescue long-term synaptic plasticity.•7g attenuates stereotyped behavior in a mouse model of Fragile X syndrome.
