Valuable Scaffolds Research Articles

An amphipathic cyclic tetrapeptide scaffold containing halogenated β2,2‐amino acids with activity against multiresistant bacteria

The present study describes the synthesis and biological studies of a small series of head-to-tail cyclic tetrapeptides of the general structure c(Lys-β2,2 -Xaa-Lys) containing one lipophilic β2,2 -amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram-positive and gram-negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β-lactamase-carbapenemase (ESBL-CARBA) production. Toxicity was determined against human red blood cells. The most potent peptides showed high activity against the gram-positive clinical isolates with minimum inhibitory concentrations of 4-8μg/mL and low haemolytic activity. The combination of high antimicrobial activity and low toxicity shows that these cyclic tetrapeptides containing lipophilic β2,2 -amino acids form a valuable scaffold for designing novel antimicrobial agents.

Organocatalytic Asymmetric Cascade Reactions Based on Gamma-Nitro Carbonyl Compound.

The significant advancements in asymmetric organocascade reactions have been accomplished during the past decades, paving the way to the efficient and stereoselective construction of structurally complex scaffolds from simple and readily available starting materials. Nitro-containing cyclic compounds have become a privileged molecular library given their broad and promising activities in various therapeutic areas. In various approaches to build these valuable scaffolds, the utility of γ-nitrocarbonyl intermediates is one of the most efficient approaches due to its high efficiency, reliability and versatility. The strategies and catalyst systems described here highlight recent advances in the enantioselective synthesis of nitro-containing cyclic molecules via organocascade strategies based on γ-nitrocarbonyl intermediates. Various organocatalysts with distinct activation modes have found application in providing these sophisticated compounds. This review is organized according to the types of organocatalyst. These methods are of importance for the construction of complex chiral cyclic frameworks and the design of new pharmaceutical compounds. We believe that compounds based on nitro-containing cyclic skeletons have the potential to provide novel therapeutic agents and useful biological tools.

Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition.

Hydroxypyridinethiones (HOPTOs) are strong ligands for metal ions and potentially useful pharmacophores for inhibiting metalloenzymes relevant to human disease. However, HOPTOs have been sparingly used in drug discovery efforts due, in part, to concerns that this scaffold will act as apromiscuous, non-selective metalloenzyme inhibitor, as well as possesspoor pharmacokinetics (PK), which may undermine drug candidates containing this functional group. To advance HOPTOs as a useful pharmacophore for metalloenzyme inhibitors, a library of 22 HOPTO isostere compounds has been synthesized and investigated. This library demonstrates that it is possible to maintain the core metal-binding pharmacophore (MBP) while generating diversity in structure, electronics, and PK properties. This HOPTO library has been screened against a set of four different metalloenzymes, demonstrating that while the same metal-binding donor atoms are maintained, there is a wide range of activity between metalloenzyme targets. Overall, this work shows that HOPTO isosteres are useful MBPs and valuable scaffolds for metalloenzyme inhibitors.

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A.

Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

AbstractNatural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4‐oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow‐up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4‐oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

Diversity-Oriented Approach to N-Heterocyclic Compounds from α-Phenyl-β-enamino Ester via a Mitsunobu-Michael Reaction Sequence.

Herein we delineate a novel route for the diastereoselective construction of diversely substituted N-heterocyclic ring systems as valuable scaffolds for natural products and pharmaceuticals, starting from an easily accessible prochiral α-phenyl-β-enamino ester. The reaction sequence relies on the unexplored reactivity of α-phenyl-β-enamino ester as a nucleophilic partner in the Mitsunobu reaction to forge the N-tethered alkene-alcohol/thiol/amine intermediate, which was subjected to an intramolecular hetero-Michael addition reaction under mild conditions to furnish the respective N-heterocyclic compounds embedded with an exocyclic chiral center in high yields and excellent diastereoselectivities. The methodology is amenable for a broad range of substrates based on a metal-free approach.

De novo transcriptomic analysis of the venomous glands from the scorpion Heterometrus spinifer revealed unique and extremely high diversity of the venom peptides

Scorpion, as an ancient species, has been widely used on dozens of human diseases in traditional Chinese Medicine. Although the scorpion venom from the Buthidae family with the potent toxicity attracts more interests, toxins from the non-Buthidae family draw great attention as well because of its abundance and complexity even without harm to mammals. Moreover, several toxic components of scorpion venom have been identified as valuable scaffolds for the drug design and development. Using the Next Generation Sequencing (NGS) technique, here we reported the transcriptome of the venomous glands of Heterometrus spinifer, a non-Buthidae scorpion that only a few toxic and complete components have been identified known-to-date. The total mRNA extracted from the venomous glands of H. spinifer was subjected to illumina sequencing with a strategy of de novo assembly, and a total of 54 189 transcripts were unigenes from a total of 88 311 600 determined reads. We annotated 18 567 (34.26%) unigenes from NR database, 12 258 (22.62%) from SWISSPROT database, 11 161 (20.60%) from GO database, 10 159 (18.75%) from COG database and 5059 (9.34%) from KEGG database, respectively. 2843 unigenes were further selected against the toxin-related sub-database of SWISSPROT. After removing the redundancy, 13 common toxin-related subfamilies with 62 unigenes were manually confirmed, including 8 K-toxins, 1 calcin, 3 Imperatoxin I-like, 2 La1-like, 1 scorpin-like, 3 antimicrobial peptides, two types of protease inhibitors such as 8 Kunitz-type protease inhibitors and 3 Ascaris-type protease inhibitors, and 33 proteases including 16 serine proteinases, 7 phospholipases, 5 metalloproteases, 3 hyaluronidases and 2 phosphatases. Our report is the first transcriptomic analyses of venomous glands from the scorpion H. spinifer, serving as a public information platform for the development of novel bio-therapeutics.

Palladium-catalyzed denitrogenative cycloadditions and alkenylations of benzotriazoles with alkynes

Palladium-catalyzed denitrogenative cycloadditions and alkenylations of benzotriazoles with alkynes have been achieved under different conditions, which enable the divergent syntheses of three types of valuable scaffolds.

Anticonvulsant Activity of 3-imidazolylflavanones and Their Flexible Analogs: 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanones as New Lead Compounds

In the search for new anticonvulsants, the (arylalkyl)azole framework has been considered as a valuable scaffold. Accordingly, a series of trans-3-imidazolylflavanones (1 – 15) and their flexible analogs 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanones (16 – 19) containing an (arylalkyl)azole substructure were evaluated for their anticonvulsant activities by using pentylenetetrazole (PTZ) and maximal electroshock (MES)induced seizure tests. Also, the effect of substituent on the pendant phenyl ring and the impact of structural flexibility were investigated. The obtained results revealed that 2-(azol-1-yl)ethanone derivatives 16 – 18 exhibited 50 – 100% protection against MES-induced seizures at a dose of 100 mg/kg. Particularly, compound 16 was found to be significantly active at doses of 10 and 30 mg/kg (25 and 75% protection, respectively). This compound showed full protection at a dose of 100 mg/kg. The structure – activity relationship study revealed that the dichloro substituent in the secondary phenyl ring can improve the anticonvulsant activity. Furthermore, disconnection of the C2 – C3 bond of flavanone in trans-3-imidazolylflavanones results in flexible analogs 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanones with improved anticonvulsant activity. Docking study of representative compound 16 with possible targets involved in convulsions demonstrated that the GABAA receptors can be considered as the main target for anticonvulsant activity of compound 16.

Recent trends in ring opening of epoxides with sulfur nucleophiles.

Thiolysis of epoxides offers an efficient and simple synthetic approach to access [Formula: see text]-hydroxy sulfides which are valuable scaffold in the synthesis of various important molecules in medicinal chemistry. This review article presents a recent compilation of the synthetic approaches developed after 2000 for the thiolysis of epoxides.

Rationally designed hecogenin thiosemicarbazone analogs as novel MEK inhibitors for the control of breast malignancies

Natural products have documented oncology success history as valuable scaffolds for selective target modulation. Herein, the sapogenin hecogenin (1) was screened for its anti-breast cancer inhibitory capacity using in vitro assays, including proliferation, cytotoxicity, migration, invasion assays, and Western blotting. The results identified 1 as a propitious hit with modest activities attributed to the concurrent down-regulation of mitogen activated protein kinase kinase/extracellular signal-regulated kinase (MEK) distinctive downstream effectors. Guided by in silico 3D-structural insights of MAPK kinase domain, an extension strategy was adopted at 1’s C-3 and C-12 aimed at the design of novel hecogenin-based analogs with improved target binding affinity. Thirty-three analogs were prepared and tested, among which hecogenin 12-(3′-methylphenyl thiosemicarbazone) (30) displayed the most potent selective anticancer effects. Analog 30 demonstrated antiproliferative, antimigratory and anti-invasive activities at low μM level, compared to the negligible effect on the non-tumorigenic MCF-10A mammary epithelial cells. Durable regression of breast tumor xenografts in athymic nude mice was observed after treatments with 30, compared to its parent hecogenin at the same dose regimen, confirmed the hit-to-lead promotion of this analog. Hecogenin-12-thiosemicarbazones, represented by 30, is a novel MEK inhibitory lead class to control breast neoplasms.

Al(III) chloride catalyzed multi-component domino strategy: Synthesis of library of dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones

Tetrazolo[1,5-a]pyrimidines are well recognized and valuable scaffolds in drug discovery. In the current manuscript, we demonstrated AlCl3 catalyzed synthesis of series of dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones via a modified Biginelli type multi-component reaction of 5-aminotetrazole, aldehyde and diverse active methylene components such as acetophenone/alkylacetoacetates/dimedone. This provides an efficient route to construct highly functionalized dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones directly from readily available starting materials.

Anonymity as an instructional scaffold in peer assessment: its effects on peer feedback quality and evolution in students’ perceptions about peer assessment skills

Although previous research has indicated that providing anonymity is an effective way to create a safe peer assessment setting, continuously ensuring anonymity prevents students from experiencing genuine two-way interactive feedback dialogues. The present study investigated how installing a transitional approach from an anonymous to a non-anonymous peer assessment setting can overcome this problem. A total of 46 bachelor’s degree students in Educational Studies participated in multiple peer assessment cycles in which groups of students assessed each other’s work. Both students’ evolution in peer feedback quality as well as their perceptions were measured. The content analysis of the peer feedback messages revealed that the quality of peer feedback increased in the anonymous phase, and that over time, the feedback in the consecutive non-anonymous sessions was of similar quality. The results also indicate that the transitional approach does not hinder the perceived growth in peer feedback skills, nor does it have a negative impact on their general conceptions towards peer assessment. Furthermore, students clearly differentiated between their attributed importance of anonymity and their view on the usefulness of a transitional approach. The findings suggest that anonymity can be a valuable scaffold to ease students’ importance level towards anonymity and their associated need for practice.

Chalcone: A Valuable Scaffold Upgrading by Green Methods

Chalcones are naturally occurring α,β-unsaturated carbonyl compounds owning a wide range of pharmaceutical and industrial applications. They are also key precursors in the biosynthesis of other flavonoids and in the synthesis of many biologically valuable heterocyclic compounds (e.g., benzothiazepines, pyrazolines and flavones). These facts stimulate vast interest in their synthesis and transformation among organic and medicinal chemists. Because of the increasing attention to environmental pollution in our society, the application of eco-friendly synthetic methods is starting to be chemists’ first choice. This review unveils the green methods employed in the transformation of chalcones focusing on biocatalysis, though the use of other so-called green strategies will be mentioned as well. The versatility, efficiency and reactional conditions as well as the advantages and disadvantages of these approaches will be disclosed. Interesting results such as the fact that biocatalysis with microorganisms leads to...

Development of 2-Methoxyhuprine as Novel Lead for Alzheimer's Disease Therapy.

Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer’s disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors—THA and (−)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.

Synthesis and biological evaluation of quinazolinone-based hydrazones with potential use in Alzheimer’s disease

Discovering multifunctional agents for the treatment of Alzheimer’s disease (AD) is an attractive therapeutic approach. BACE1 (β-site amyloid precursor protein cleaving enzyme 1) inhibitors may play a pivotal role in treating AD. Therefore, the discovery of novel non-peptide BACE1 inhibitors with desirable blood brain barrier permeability is a favorable approach for treatment. Moreover, the antioxidant potential of a drug could serve as an added value for designing dual-acting therapeutic agents. Here, we report the design, synthesis and biological evaluation of quinazolinone-hydrazone derivatives as new multi-target candidates for the treatment of AD. The compounds were investigated for their in vitro BACE1 inhibitory potential using a FRET-based enzymatic assay and also screened for antioxidant activity using DPPH. Among them, compound 4h bearing a 2,3-dichlorophenyl moiety showed the highest activity with an IC50 value of 3.7μM against BACE1. In addition, compound 4i with a 2,4-dihydroxyphenyl scaffold demonstrated moderate BACE1 inhibitory activity (IC50=27.6μM) with a significant antioxidant effect (IC50=8.4μM). Furthermore, docking studies revealed strong interaction between compound 4h and the key residues of BACE1 active site. These results demonstrate that quinazolinone-hydrazone derivatives represent a valuable scaffold for the discovery of novel non-peptidic BACE1 inhibitors.

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold.

The review highlights the hydantoin syntheses presented from the point of view of the preparation methods. Novel synthetic routes to various hydantoin structures, the advances brought to the classical methods in the aim of producing more sustainable and environmentally friendly procedures for the preparation of these biomolecules, and a critical comparison of the different synthetic approaches developed in the last twelve years are also described. The review is composed of 95 schemes, 8 figures and 528 references for the last 12 years and includes the description of the hydantoin-based marketed drugs and clinical candidates.

Late-Stage C–H Arylation of Thiazolo[5,4-f]quinazolin-9(8H)-one Backbone: Synthesis of an Array of Potential Kinase Inhibitors

Driven by the need of structural modification to establish structure-activity relationships, the regioselective C–H bond activation of thiazolo[5,4-f]quinazolin-9(8H)-one backbone has been developed to furnish the corresponding C2-arylated valuable scaffold. This strategy provides a synthetically streamlined and useful route for late-stage diversification of this attractive skeleton, required in drug discovery. A more eco-friendly synthesis of thiazolo[5,4-f]quinazolin-9(8H)-ones is also described giving access to these aforementioned compounds in a facile manner.

Phosphine-Mediated Sequential Annulation Reaction: Access to Functionalized Benzofurans and 4,5-Dihydrobenzofurans.

A new strategy for the facile access to multi-functionalized benzofurans and 4,5-dihydrobenzofurans has been explored. The advantages of the present protocol include readily obtainable starting materials, mild and metal-free conditions, expedient and practical processes, excellent yields, and easy scale-up. The reaction demonstrated high efficiency to construct two rings in a single step. The zwitterionic intermediate generated from the conjugated attack of PPh3 to the ene-yne-ketone was proposed to be the key intermediate toward these valuable scaffolds.

Impact of the amino acid sequence on the conformation of side chain lactam-bridged octapeptides.

Synthetic helical peptides are valuable scaffolds for the development of modulators of protein-protein interactions involving helical motifs. Backbone-to-side chain or side chain-to-side chain constraints have been and still are intensively exploited to stabilize short α-helices. Very often, these constraints have been combined with backbone modifications induced by Cα-tetrasubstituted, β-, or γ-amino acids, which facilitate the α-peptide or α/β/γ-peptide adopting an α-helical conformation. In this work, we investigated the helical character of octapeptides that were cyclized by a Lys-Asp-(i,i+4)-lactam bridge. We started with two sequences extracted from the helix-loop-helix region of the Id proteins, which are inhibitors of cell differentiation during development and in cancer. Nineteen analogs containing the lactam bridge at different positions and displaying different amino acid core triads (i+1,2,3) as well as outer residues were prepared by solid-phase methodology. Their conformation in water and water/2,2,2-trifluoroethanol mixtures was investigated by circular dichroism (CD) spectroscopy. The cyclopeptides could be grouped in helix-prone and non-helix-prone structures. Both the amino acid core triad (i+1,2,3) and the pendant residues positively or negatively affected the formation of a helical structure. Computational studies based on the NMR-derived helical structure of a cyclopeptide containing Aib at position (i+2) of the triad were generally in agreement with the secondary structure propensity of the cyclopeptides observed by CD spectroscopy. In conclusion, the Lys-Asp-(i,i+4)-lactam bridge may succeed or fail in the stabilization of short helices, depending on the primary structure. Moreover, computational methods may be valuable tools to discriminate helix-prone from non-helix-prone peptide-based macrolactams. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.