F-Based Small Group Decoration of Heteroarenes via C-H Activation: Medicinal Chemistry Rationale and late-stage Synthetic Methods

2021 ◽  
Vol 25 ◽  
Author(s):  
Paolo Ronchi ◽  
Sara Guariento ◽  
Daniele Pala ◽  
Daniela Pizzirani ◽  
Claudio Fiorelli ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Group ◽  
Small Groups ◽  
Late Stage ◽  
Medicinal Chemistry ◽  
Synthetic Methods ◽  
Type Reaction ◽  
Approved Drugs ◽  
Chemistry Community

: The use of F-based decorations in drug discovery started from the development of fluorocorticoids and fluorochinolones (1950s and 1980s, respectively), and has resulted in about 20% of approved drugs on the Market containing fluorine. From a medicinal chemistry perspective, the installation of F-based small groups (e.g., CF3, -CF2H, -OCF3, -OCF2H, -SCF3, -SCF2H) necessarily impacts on physicochemical, pharmacokinetics, pharmacodynamics and toxicological properties of small molecules. Accordingly, a huge interest in this topic is constantly arising in the medicinal chemistry community. Focusing on heteroarenes, the synthetic access to these substitutions is guaranteed by a number of effective reactions such as Minisci-type reaction, photochemistry or electrochemistry C-H activation. The aim of this work is to analyze the rationale in using these groups in medicinal chemistry and highlight the currently available synthetic toolbox of C-H activation for their introduction on heteroarenes of pharmaceutical interest. A particular focus has been given to those procedures amenable to the late-stage functionalisation process.

scholarly journals A New Big-Data Paradigm for Target Identification and Drug Discovery

2017 ◽  
Author(s):  
Neel S. Madhukar ◽  
Prashant K. Khade ◽  
Linda Huang ◽  
Kaitlyn Gayvert ◽  
Giuseppe Galletti ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Clinical Application ◽  
Small Molecule ◽  
Target Identification ◽  
Clinical Development ◽  
Data Types ◽  
Public Data ◽  
Drug Target Identification ◽  
Approved Drugs

AbstractDrug target identification is one of the most important aspects of pre-clinical development yet it is also among the most complex, labor-intensive, and costly. This represents a major issue, as lack of proper target identification can be detrimental in determining the clinical application of a bioactive small molecule. To improve target identification, we developed BANDIT, a novel paradigm that integrates multiple data types within a Bayesian machine-learning framework to predict the targets and mechanisms for small molecules with unprecedented accuracy and versatility. Using only public data BANDIT achieved an accuracy of approximately 90% over 2000 different small molecules – substantially better than any other published target identification platform. We applied BANDIT to a library of small molecules with no known targets and generated ∼4,000 novel molecule-target predictions. From this set we identified and experimentally validated a set of novel microtubule inhibitors, including three with activity on cancer cells resistant to clinically used anti-microtubule therapies. We next applied BANDIT to ONC201 – an active anti- cancer small molecule in clinical development – whose target has remained elusive since its discovery in 2009. BANDIT identified dopamine receptor 2 as the unexpected target of ONC201, a prediction that we experimentally validated. Not only does this open the door for clinical trials focused on target-based selection of patient populations, but it also represents a novel way to target GPCRs in cancer. Additionally, BANDIT identified previously undocumented connections between approved drugs with disparate indications, shedding light onto previously unexplained clinical observations and suggesting new uses of marketed drugs. Overall, BANDIT represents an efficient and highly accurate platform that can be used as a resource to accelerate drug discovery and direct the clinical application of small molecule therapeutics with improved precision.

scholarly journals Synthesis of Imidazole-Based Medicinal Molecules Utilizing the van Leusen Imidazole Synthesis

2020 ◽  
Vol 13 (3) ◽  
pp. 37 ◽  
Author(s):  
Xunan Zheng ◽  
Zhengning Ma ◽  
Dawei Zhang
Keyword(s):  
Drug Discovery ◽  
Chemical Synthesis ◽  
Small Molecules ◽  
Medicinal Chemistry ◽  
Biological Activities ◽  
Structural Features ◽  
Pharmaceutical Companies ◽  
Recent Developments ◽  
Van Leusen Reaction

Imidazole and its derivatives are one of the most vital and universal heterocycles in medicinal chemistry. Owing to their special structural features, these compounds exhibit a widespread spectrum of significant pharmacological or biological activities, and are widely researched and applied by pharmaceutical companies for drug discovery. The van Leusen reaction based on tosylmethylisocyanides (TosMICs) is one of the most appropriate strategies to synthetize imidazole-based medicinal molecules, which has been increasingly developed on account of its advantages. In this review, we summarize the recent developments of the chemical synthesis and bioactivity of imidazole-containing medicinal small molecules, utilizing the van Leusen imidazole synthesis from 1977.

scholarly journals Gliptin Repurposing for COVID-19

2020 ◽  
Author(s):  
Matthew Groves ◽  
Alexander Domling ◽  
Angel Jonathan Ruiz Moreno ◽  
Atilio Reyes Romero ◽  
Constantinos Neochoritis ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Drug Class ◽  
De Novo ◽  
Drug Repurposing ◽  
Therapeutic Modality ◽  
Antidiabetic Drug ◽  
Short Term ◽  
Computational Screening ◽  
Approved Drugs

<i>De novo</i> drug discovery of any therapeutic modality (e.g. antibodies, vaccines or small molecules) historically takes years from idea/preclinic to the market and it is therefore not a short-term solution for the current SARS-CoV-2 pandemic. Therefore, drug repurposing – the discovery novel indication areas for already approved drugs - is perhaps the only approach able to yield a short term relieve. Here we describe computational screening results suggesting that certain members of the drug class of gliptins are inhibitors of the two SARS-CoV-2 proteases 3CLpro and PLpro. The oral bioavailable antidiabetic drug class of gliptins are safe and have been introduced clinically since 2006 and used by millions of patients since then. Based on our repurposing hypothesis the nitrile containing gliptins deserve further investigation as potential anti-COVID19 drugs.

Backbone-Enabled Peptide Macrocyclization through Late-Stage Palladium-Catalyzed C–H Activation

Synlett ◽  
2019 ◽  
Vol 31 (03) ◽  
pp. 199-204 ◽  
Author(s):  
Zengbing Bai ◽  
Huan Wang
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Late Stage ◽  
Cyclic Peptides ◽  
Medicinal Chemistry ◽  
Materials Science ◽  
Three Dimensional ◽  
Chemical Methods ◽  
New Methods ◽  
Palladium Catalyzed

Peptide macrocycles are widely used in fields ranging from medicinal chemistry to materials science. Efficient chemical methods for the synthesis of cyclic peptides with novel three-dimensional structures are highly desired to facilitate the development of this unique class of compounds. However, the range of methods available for constructing peptide macrocycles is limited compared with that for small molecules. We recently developed new methods for synthesizing highly constrained cyclic peptides with C–C crosslinks through Pd-catalyzed C–H activation reactions. These methods use endogenous backbone amides as directing groups and, therefore, have the potential for use in late-stage functionalization of peptide natural products.

scholarly journals Gliptin Repurposing for COVID-19

2020 ◽  
Author(s):  
Matthew Groves ◽  
Alexander Domling ◽  
Angel Jonathan Ruiz Moreno ◽  
Atilio Reyes Romero ◽  
Constantinos Neochoritis ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Drug Class ◽  
De Novo ◽  
Drug Repurposing ◽  
Therapeutic Modality ◽  
Antidiabetic Drug ◽  
Short Term ◽  
Computational Screening ◽  
Approved Drugs

<i>De novo</i> drug discovery of any therapeutic modality (e.g. antibodies, vaccines or small molecules) historically takes years from idea/preclinic to the market and it is therefore not a short-term solution for the current SARS-CoV-2 pandemic. Therefore, drug repurposing – the discovery novel indication areas for already approved drugs - is perhaps the only approach able to yield a short term relieve. Here we describe computational screening results suggesting that certain members of the drug class of gliptins are inhibitors of the two SARS-CoV-2 proteases 3CLpro and PLpro. The oral bioavailable antidiabetic drug class of gliptins are safe and have been introduced clinically since 2006 and used by millions of patients since then. Based on our repurposing hypothesis the nitrile containing gliptins deserve further investigation as potential anti-COVID19 drugs.

scholarly journals Fluorine-Containing Chrysin Derivatives

2019 ◽  
Vol 14 (9) ◽  
pp. 1934578X1987892
Author(s):  
Yue Zhu ◽  
Xu Yao ◽  
Jin Long ◽  
Rong Li ◽  
Yi Liu ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Fluorine Atom ◽  
Medicinal Chemistry ◽  
Antiviral Drug ◽  
Antimicrobial Activities ◽  
Synthetic Methods ◽  
Reaction Process ◽  
Great Role ◽  
Substituent Group

Chrysin, a flavonoid, has played a great role in the fields of anticancer, antibacterial, and antiviral drug discovery. A large number of chrysin derivatives have been synthesized recently. The fluorine atom represents an important substituent group for a great number of natural products and pharmaceuticals. Taking into account the importance of both chrysin and the fluorine atom in medicinal chemistry, the synthesis of fluorine-containing chrysin derivatives has gained great interest. Chemically, the synthetic methods for these new chrysin derivatives have also been developed rapidly. In recent years, research on their synthesis has been focused on speeding up the reaction process by changing the catalyst. Biologically, the purpose of introducing fluorine into chrysin was to improve its lipophilicity, but today it is mainly focused on the enhancement and improvement of either its anticancer or antimicrobial activities by incorporating the special properties of fluorine atoms. In this review, synthetic methods for the introduction of fluorine atoms into chrysin are summarized, and their anticancer, antibacterial, antiviral, and hypoglycemic effects are discussed.

scholarly journals Recent Advances in the Synthesis of Piperazines: Focus on C–H Functionalization

Organics ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 337-347
Author(s):  
Carolina Durand ◽  
Michal Szostak
Keyword(s):  
Drug Discovery ◽  
Medicinal Chemistry ◽  
Structural Diversity ◽  
Synthetic Methods ◽  
Nitrogen Heterocycle ◽  
Piperazine Ring ◽  
The Third ◽  
Recent Advances ◽  
Made In

Piperazine ranks as the third most common nitrogen heterocycle in drug discovery, and it is the key component of several blockbuster drugs, such as Imatinib (also marketed as Gleevec) or Sildenafil, sold as Viagra. Despite its wide use in medicinal chemistry, the structural diversity of piperazines is limited, with about 80% of piperazine-containing drugs containing substituents only at the nitrogen positions. Recently, major advances have been made in the C–H functionalization of the carbon atoms of the piperazine ring. Herein, we present an overview of the recent synthetic methods to afford functionalized piperazines with a focus on C–H functionalization.

Medicinal Chemistry Database GDBMedChem

2019 ◽  
Author(s):  
Mahendra Awale ◽  
Finton Sirockin ◽  
Nikolaus Stiefl ◽  
Jean-Louis Reymond
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Medicinal Chemistry ◽  
3D Visualization ◽  
Molecular Size ◽  
Similarity Searching ◽  
Complex Molecules ◽  
Synthetic Accessibility ◽  
Simple Chemical ◽  
Reduced Complexity

<div>The generated database GDB17 enumerates 166.4 billion possible molecules up to 17 atoms of C, N, O, S and halogens following simple chemical stability and synthetic feasibility rules, however medicinal chemistry criteria are not taken into account. Here we applied rules inspired by medicinal chemistry to exclude problematic functional groups and complex molecules from GDB17, and sampled the resulting subset evenly across molecular size, stereochemistry and polarity to form GDBMedChem as a compact collection of 10 million small molecules.</div><div><br></div><div>This collection has reduced complexity and better synthetic accessibility than the entire GDB17 but retains higher sp 3 - carbon fraction and natural product likeness scores compared to known drugs. GDBMedChem molecules are more diverse and very different from known molecules in terms of substructures and represent an unprecedented source of diversity for drug design. GDBMedChem is available for 3D-visualization, similarity searching and for download at http://gdb.unibe.ch.</div>

A Revised Modular Approach to D8-THC and Derivatives Through Late-Stage Suzuki-Miyaura Cross-Coupling Reactions

2019 ◽  
Author(s):  
Victor Bloemendal ◽  
Floris P. J. T. Rutjes ◽  
Thomas J. Boltje ◽  
Daan Sondag ◽  
Hidde Elferink ◽  
...  
Keyword(s):  
Biological Activity ◽  
Late Stage ◽  
Medicinal Chemistry ◽  
Cross Coupling ◽  
Modular Approach ◽  
Coupling Reactions ◽  
One Pot ◽  
Biologically Relevant ◽  
Cross Coupling Reactions ◽  
Chemistry Research

<p>In this manuscript we describe a modular pathway to synthesize biologically relevant (–)-<i>trans</i>-Δ<sup>8</sup>-THC derivatives, which can be used to modulate the pharmacologically important CB<sub>1</sub> and CB<sub>2</sub> receptors. This pathway involves a one-pot Friedel-Crafts alkylation/cyclization protocol, followed by Suzuki-Miyaura cross-coupling reactions and gives rise to a series of new Δ<sup>8</sup>-THC derivatives. In addition, we demonstrate using extensive NMR evidence that similar halide-substituted Friedel-Crafts alkylation/cyclization products in previous articles were wrongly assigned as the para-isomers, which also has consequence for the assignment of the subsequent cross-coupled products and interpretation of their biological activity. </p> <p>Considering the importance of the availability of THC derivatives in medicinal chemistry research and the fact that previously synthesized compounds were wrongly assigned, we feel this research is describing a straightforward pathway into new cannabinoids.</p>

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