Combinatorial biosynthesis for the generation of new-to-nature peptide antimicrobials

Metal-, and Organocatalyst-Free One-Pot Assembly of Chiral Aza-Tricyclic Molecules: Creating Six Contiguous Stereocenters from 2-D-Structures and an Amino Acid

10.26434/chemrxiv.12757943.v1 ◽

2020 ◽

Author(s):

Dung Do

Keyword(s):

Amino Acid ◽

Chemical Space ◽

Structural Diversity ◽

Therapeutic Agents ◽

Chiral Molecules ◽

One Pot ◽

Complex Molecules ◽

Chiral Catalyst ◽

Chiral Complex ◽

Free Process

Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.1 Practically, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for desired reactions. As a result, developing a method that enables rapid assembly of chiral complex molecules under metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward route to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“subcatalyst”) dual role of the intermediate enhances </a><a>the coordinational proximity of the chiral substrate and catalyst</a> in the key Aza-Michael/Michael cascade resulting in a substantial steric discrimination and an excellent overall diastereoselectivity. Whereas the “subcatalyst” (hidden catalyst) is not present in the reaction’s initial components, which renders a chiral catalyst-free process, it is strategically produced to promote sequential self-catalyzed reactions. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules and aid for the quest to create next generation of therapeutic agents.

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Flavonoids from the Genus Euphorbia: Isolation, Structure, Pharmacological Activities and Structure–Activity Relationships

Pharmaceuticals ◽

10.3390/ph14050428 ◽

2021 ◽

Vol 14 (5) ◽

pp. 428

Author(s):

Douglas Kemboi Magozwi ◽

Mmabatho Dinala ◽

Nthabiseng Mokwana ◽

Xavier Siwe-Noundou ◽

Rui W. M. Krause ◽

...

Keyword(s):

Therapeutic Potential ◽

Antioxidant Properties ◽

Structure Activity Relationship ◽

Biological Properties ◽

Therapeutic Agents ◽

Skeletal Structure ◽

Activity Relationship ◽

Hydroxyl Groups ◽

Structure Activity ◽

Review Reports

Plants of the genus Euphorbia are widely distributed across temperate, tropical and subtropical regions of South America, Asia and Africa with established Ayurvedic, Chinese and Malay ethnomedical records. The present review reports the isolation, occurrence, phytochemistry, biological properties, therapeutic potential and structure–activity relationship of Euphorbia flavonoids for the period covering 2000–2020, while identifying potential areas for future studies aimed at development of new therapeutic agents from these plants. The findings suggest that the extracts and isolated flavonoids possess anticancer, antiproliferative, antimalarial, antibacterial, anti-venom, anti-inflammatory, anti-hepatitis and antioxidant properties and have different mechanisms of action against cancer cells. Of the investigated species, over 80 different types of flavonoids have been isolated to date. Most of the isolated flavonoids were flavonols and comprised simple O-substitution patterns, C-methylation and prenylation. Others had a glycoside, glycosidic linkages and a carbohydrate attached at either C-3 or C-7, and were designated as d-glucose, l-rhamnose or glucorhamnose. The structure–activity relationship studies showed that methylation of the hydroxyl groups on C-3 or C-7 reduces the activities while glycosylation loses the activity and that the parent skeletal structure is essential in retaining the activity. These constituents can therefore offer potential alternative scaffolds towards development of new Euphorbia-based therapeutic agents.

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A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules containing six contiguous stereocenters

10.26434/chemrxiv.12757943.v2 ◽

2020 ◽

Author(s):

Dung Do

Keyword(s):

Chemical Space ◽

Structural Diversity ◽

Therapeutic Agents ◽

Chiral Molecules ◽

One Pot ◽

Complex Molecules ◽

Chiral Complex ◽

Enamine Catalysis ◽

Daunting Challenge

Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.1 In practice, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for a desired reaction. As a result, developing a method that enables rapid assembly of chiral complex molecules under a metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward one-pot procedure to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“sub-catalyst”) dual role of the intermediate was displayed in its aza-Michael/Michael cascade reaction with an </a>α,β-unsaturated aldehyde under an iminium/enamine catalysis. <a>The enhanced co-ordinational proximity of the chiral substrate and catalyst</a> in the transition state resulted in a substantial steric discrimination and an excellent overall diastereoselectivity. Aza-tricylic molecules with six contiguous stereocenters were assembled from N-alkylated aminophenols, α,β-unsaturated aldehydes and chiral α-amino acids under a hidden “sub-catalysis” where the strategically produced “sub-catalyst” does not present in initial components of the reaction. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules.

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Cheminformatics Modeling of Closantel Analogues for Treating River Blindness

10.26434/chemrxiv.11606019.v1 ◽

2020 ◽

Author(s):

Melaine A. Kuenemann ◽

Phyo Phyo Zin ◽

Sravya Kuchibhotla ◽

Denis Fourches

Keyword(s):

Active Site ◽

Structural Changes ◽

Parasitic Nematode ◽

Chemical Space ◽

Therapeutic Agents ◽

Binding Modes ◽

River Blindness ◽

Structure Activity ◽

Potential Binding ◽

Biological Target

Onchocerciasis (also known as river blindness) is a neglected tropical disease caused by the Onchocerca volvulus parasitic nematode. Currently, the only approved drug for treating this disease is ivermectin, which is a broad-spectrum antiparasitic agent. However, signs of resistance towards ivermectin have started to emerge. New therapeutic agents are thus urgently needed. The OvCHT1 chitinase enzyme from O. volvulus has been established as a relevant biological target for combatting river blindness. The veterinary anthelmintic drug closantel has been found to be a potent, micro-molar OvCHT1 inhibitor. Herein, we investigated the chemical space of closantel and all its synthesized analogues, focusing on the analysis of their potential binding modes towards OvCHT1. First, we conducted an unsupervised hierarchical clustering to group highly similar analogues and explore structure-activity relationships. Second, we conducted a structure-based molecular docking to predict and study the binding modes of all 57 closantel analogues in the active site of OvCHT1. Third, we screened more than 4 million lead-like compounds from the ZINC library to identify other structurally similar ligands that could potentially bind to OvCHT1. The cheminformatics analysis of the closantel analogues illustrated how minor structural changes in closantel analogues can impact their OvCHT1 activity.

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Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

Pharmaceuticals ◽

10.3390/ph13020020 ◽

2020 ◽

Vol 13 (2) ◽

pp. 20

Author(s):

Quentin Spillier ◽

Séverine Ravez ◽

Judith Unterlass ◽

Cyril Corbet ◽

Charline Degavre ◽

...

Keyword(s):

Cancer Progression ◽

Structure Activity Relationship ◽

Therapeutic Agents ◽

Activity Relationship ◽

Cancer Treatments ◽

Promising Strategy ◽

Structure Activity ◽

Phosphoglycerate Dehydrogenase ◽

Relationship Study

For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH.

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Clinical Pharmacology and Pharmacokinetics of Fluoxetine: A Review

The British Journal of Psychiatry ◽

10.1192/s0007125000297286 ◽

1988 ◽

Vol 153 (S3) ◽

pp. 47-50 ◽

Cited By ~ 80

Author(s):

R. F. Bergstrom ◽

L. Lemberger ◽

N. A. Farid ◽

R. L. Wolen

Keyword(s):

Clinical Pharmacology ◽

Antidepressant Drug ◽

Therapeutic Agents ◽

Systematic Evaluation ◽

Pharmacological Properties ◽

Lead Compound ◽

Serotonin Uptake Inhibitors ◽

Synthetic Compounds ◽

Structure Activity ◽

Complex Process

Drugs are discovered by a variety of approaches, which include a systematic evaluation of synthetic compounds, using extensive structure activity relationships. After a lead compound which possesses desirable pharmacological properties is found, through the exhaustive screening of a variety of compounds, a number of congeners are then synthesised and tested, using specific physiological or biochemical models of therapeutic agents. The discovery of fluoxetine involved this complex process, and led to the description in the literature of one of the first selective serotonin uptake inhibitors (Wonget al, 1974); it was subsequently tested clinically, and these studies demonstrated its effectiveness and safety as an antidepressant drug (Chouinard, 1985). This paper reviews the published information relevant to fluoxetine's pharmacology and pharmacokinetics in man.

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Prediction of antiprion activity of therapeutic agents with structure–activity models

Molecular Diversity ◽

10.1007/s11030-013-9477-3 ◽

2013 ◽

Vol 18 (1) ◽

pp. 133-148 ◽

Cited By ~ 6

Author(s):

Katja Venko ◽

Špela Župerl ◽

Marjana Novič

Keyword(s):

Therapeutic Agents ◽

Structure Activity ◽

Activity Models

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Quantitative structure–activity relationships study of potent pyridinone scaffold derivatives as HIV-1 integrase inhibitors with therapeutic applications

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633617500389 ◽

2017 ◽

Vol 16 (05) ◽

pp. 1750038 ◽

Cited By ~ 6

Author(s):

Abolfazl Barzegar ◽

Hossein Hamidi

Keyword(s):

Therapeutic Agents ◽

Quantitative Structure ◽

Structure Activity Relationships ◽

Structure Activity ◽

Qsar Models ◽

Stepwise Procedure ◽

Quantitative Structure Activity Relationships ◽

Anti Hiv ◽

Hiv 1 ◽

Mlr Model

Human immunodeficiency virus-1 (HIV-1) integrase appears to be a crucial target for developing new anti-HIV-1 therapeutic agents. Different quantitative structure–activity relationships (QSARs) algorithms have been used in order to develop efficient model(s) to predict the activity of new pyridinone derivatives against HIV-1 integrase. Multiple linear regression (MLR) and combined principal component analysis (PCA) with MLR have been applied to build QSAR models for a set of new pyridinone derivatives as potent anti-HIV-1 therapeutic agents. Four different approaches based on MLR method including; concrete-MLR, stepwise-MLR, concrete PCA–MLR and stepwise PCA–MLR were utilized for this aim. Twenty two different sets of descriptors containing 1613 descriptors were constructed for each optimized molecule. Comparison between predictability of the “concrete” and “stepwise” procedure in two different algorithms of MLR and PCA models indicated the advantage of the stepwise procedure over that of the simple concrete method. Although the PCA was employed for dimension reduction, using stepwise PCA–MLR model showed that the method has higher ability to predict the compounds’ activity. The stepwise PCA–MLR model showed highly validated statistical results both in fitting and prediction processes ([Formula: see text] and [Formula: see text]). Therefore, using stepwise PCA approach is suitable to remove ineffective descriptors, which results in remaining efficient descriptors for building good predictability stepwise PCA–MLR. The stepwise hybrid approach of PCA–MLR may be useful in derivation of highly predictive and interpretable QSAR models.

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Quantitative Structure-Activity Relationships (QSARs) for Materials Science

MRS Proceedings ◽

10.1557/proc-700-s7.5 ◽

2001 ◽

Vol 700 ◽

Cited By ~ 4

Author(s):

Krishna Rajan ◽

Changwon Suh ◽

Arun Rajagopalan ◽

Xiang Li

Keyword(s):

Organic Chemistry ◽

Materials Science ◽

Molecular Level ◽

Combinatorial Synthesis ◽

Quantitative Structure ◽

New Materials ◽

Structure Activity Relationships ◽

Structure Activity ◽

Computational Aspects ◽

Quantitative Structure Activity Relationships

AbstractThe field of combinatorial synthesis and “artificial intelligence” in materials science is still in its infancy. In order to develop and accelerated strategy in the discovery of new materials and processes, requires the need to integrate both the experimental aspects of combinatorial synthesis with the computational aspects of information based design of materials. In biology and organic chemistry, this has been accomplished by developing descriptors which help to specify “quantitative structure- activity relationships” at the molecular level. If materials science is to adopt these strategies as well, a similar framework of “QSARs” is required. In this paper, we outline some approaches that can lay the foundations for QSARs in materials science.

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A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules containing six contiguous stereocenters

10.26434/chemrxiv.12757943 ◽

2020 ◽

Author(s):

Dung Do

Keyword(s):

Chemical Space ◽

Structural Diversity ◽

Therapeutic Agents ◽

Chiral Molecules ◽

One Pot ◽

Complex Molecules ◽

Chiral Complex ◽

Enamine Catalysis ◽

Daunting Challenge

Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.1 In practice, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for a desired reaction. As a result, developing a method that enables rapid assembly of chiral complex molecules under a metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward one-pot procedure to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“sub-catalyst”) dual role of the intermediate was displayed in its aza-Michael/Michael cascade reaction with an </a>α,β-unsaturated aldehyde under an iminium/enamine catalysis. <a>The enhanced co-ordinational proximity of the chiral substrate and catalyst</a> in the transition state resulted in a substantial steric discrimination and an excellent overall diastereoselectivity. Aza-tricylic molecules with six contiguous stereocenters were assembled from N-alkylated aminophenols, α,β-unsaturated aldehydes and chiral α-amino acids under a hidden “sub-catalysis” where the strategically produced “sub-catalyst” does not present in initial components of the reaction. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules.

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