Role of Chemistry in Lead Discovery

Dolle, Roland E.; Worm, Karin

doi:10.1002/9780470584170.ch9

Cited by 5 publications

(1 citation statement)

References 65 publications

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“…When exploring the SAR of a series of amides, one commonly used strategy is to reverse the orientation of the amide linkage [ 32 ]. Hence we were interested in also including N-aryl-acetamide fragments in our study.…”

Section: Resultsmentioning

confidence: 99%

Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments

Sanfeliciano¹,

Schaus

2018

PLoS ONE

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The ability to rapidly assess the preferred conformation of key fragments in a structure “by visual inspection” is a very useful starting point in the process of drug design. With the ability to do so, one could address questions like: “How could we avoid planarity in a molecule?”, “Will a molecule change its conformational preference if we make it more or less basic?” or “How does this electronic repulsion affect the conformational preference in the system?” in timely fashion. In this paper, we describe how the conformational energy profile (CEP, plot of energy as a function of dihedral bond angle) of a fragment can be interpreted through the understanding the interplay between resonance stabilization, steric effects and electrostatic interactions. Fifty-nine biaryl and aryl carbonyl fragments present in oral drugs or which are close derivatives thereof were selected. Calculation of their CEPs using ab initio methodology allowed us to conclude the relative importance of these factors in the conformational preference of these fragments as follows: “steric repulsion > lone pair—lone pair repulsion > lone pair—fluorine repulsion > resonance stabilization” and to formulate “rules of thumb” that the practicing medicinal/organic chemist can apply when analysing molecules that contain these fragments.

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Section: Resultsmentioning

confidence: 99%

Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments

Sanfeliciano¹,

Schaus

2018

PLoS ONE

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Novel Solid‐phase and Solution‐phase Synthetic Methods for Trisubstituted Thieno[3,2‐d]pyrimidine Derivatives

Jeon

Kim

Lee

2016

Bulletin Korean Chem Soc

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The coupling of 7-aryl-3,4-dihydro-4-oxothieno[3,2-d]pyrimidine-2-carboxylic acid with a primary alkylamineloaded acid-sensitive methoxy benzaldehyde (AMEBA) resin, a benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP)-mediated amination reaction, and cleavage from the solid support yielded N-alkyl-4-(alkylamino)-7-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The progress of the reactions on solid phase was monitored through attenuated total reflectance-FTIR spectroscopy and was compared with representative solution-phase surrogates. Additionally, N-acylation (acid chloride, InF 3 , CH 3 CN, room temperature) and cyclization (DBN, 1,4-dioxane, 80 C) of a 3-amino-4-(4-t-butoxycarbonylphenyl) thiophene-2-carboxamide intermediate under previously unreported conditions provided 2-substituted thieno[3,2-d]pyrimidin-4(3H)-one derivatives, which were subsequently converted to 2-substituted 4-alkylamino-7-[4-(alkylaminocarbonyl)phenyl]thieno[3,2-d]pyrimidine derivatives through a reaction sequence consisting of a BOP-mediated amination reaction, t-butyl deprotection, and amide formation.

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Synthesis of Highly Functionalized Diaryl Ethers by Copper‐Mediated O‐Arylation of Phenols using Trivalent Arylbismuth Reagents

Crifar

Petiot

Ahmad

et al. 2014

Chemistry A European J

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Highly functionalized diaryl ethers were prepared by copper(II) acetate mediated O-arylation reaction of phenols using trivalent organobismuthanes. The reaction is performed under simple conditions and tolerates a wide diversity of functional groups on the phenol and on the organobismuth reagent. Substoichiometric amounts of catalyst can be used by performing the reaction under an oxygen atmosphere. The N-arylation of pyridones is also reported.

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Role of Chemistry in Lead Discovery

Cited by 5 publications

References 65 publications

Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments

Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments

Novel Solid‐phase and Solution‐phase Synthetic Methods for Trisubstituted Thieno[3,2‐d]pyrimidine Derivatives

Synthesis of Highly Functionalized Diaryl Ethers by Copper‐Mediated O‐Arylation of Phenols using Trivalent Arylbismuth Reagents

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