Synthesis and Biological Evaluation of CTP Synthetase Inhibitors as Potential Agents for the Treatment of African Trypanosomiasis

Tamborini, Lucia; Pinto, Andrea; Smith, Terry; Major, Louise L.; Iannuzzi, Maria C.; Cosconati, Sandro; Marinelli, Luciana; Novellino, Ettore; Presti, Leonardo Lo; Wong, Pui Ee; Barrett, Michael P.; Micheli, Carlo De; Conti, Paola

doi:10.1002/cmdc.201200304

Cited by 31 publications

(37 citation statements)

References 25 publications

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“…Out of a sample of 5560 unique centrosymmetric organic structures stored in the Cambridge Structural Database (CSD), 17,18 Dalhus & Görbitz estimate 19 that 23 % are racemates. Their occurrence falls to 16.5% in a sample of 3819 mirror-symmetric acentric space groups. Conversely, chiral space groups are hardly preferred in racemates, and -apart very few exceptions 19,20 -one anticipates inversion and/or reflection elements to be present for pairs of opposite enantiomers.…”

Section: Methodsmentioning

confidence: 90%

“…16 PYRAC (Scheme 1) crystallizes in the acentric polar space group Pca21 (n°29) with 8 formulae in cell. In fact, its asymmetric unit contains a couple of hydrogen-bonded enantiomers in distinct conformations.…”

Section: Methodsmentioning

confidence: 99%

“…PYRAC (Figure 1) was synthesized as described elsewhere. 16 Large and well-formed crystals appeared directly after resting the reaction liquor overnight at RT from a 1:1 mixture of ethyl acetate/hexane. 23 The pure compound was kept in the dark in a refrigerator at T = 4 ºC for ≈ 2.5 months.…”

Section: Methodsmentioning

confidence: 99%

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Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study

Presti

Sist

Loconte

et al. 2014

Crystal Growth & Design

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The total charge density of PYRAC, a polar (Pca21) organic racemate with Z' = 2 was derived from high-resolution single-crystal X-ray diffraction data at T = 100(2) K and periodic DFT calculations.The PYRAC asymmetric unit consists of a hydrogen-bonded pair of conformationally different enantiomers, A and Bi, where the subscript 'i' indicates a reversed absolute configuration. The lattice stability was compared with that of centrosymmetric possibly competing structures, with the aim of understanding why a non-centrosymmetric lattice framework is obtained from a racemic mixture. The likelihood of specific intermolecular recognition processes among different conformers of PYRAC in the very first stages of nucleation was investigated by DFT simulations in vacuo. Two competing, equivalent interconversion pseudorotatory paths between the most stable A and the least stable B conformers were found. It results that molecules spend most of their time (≈ 53 %) in the A conformation, while the B one is far less populated (≈ 7 %). Therefore, centrosymmetric AAi adducts are formed very frequently in the reaction liquor, while the BBi ones are rare. Nevertheless, AAi pairs produce crystal forms with cohesive energies and densities significantly less favourable than those estimated for the non-centrosymmetric heterochiral ABi ones. Therefore, preference for Z' = 2 in conjunction with non-centrosymmetric point and space groups results from the thermodynamic control of the crystallization process. The capability of forming extended hydrogen bond chains throughout the lattice appears to be a prerequisite to bind together the fundamental ABi repeating units.

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Section: Methodsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

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Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study

Presti

Sist

Loconte

et al. 2014

Crystal Growth & Design

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“…Moreover, the hydroxyl group of 2 a was easily transformed into a synthetically valuable azido group through two routine elaborations, giving 9 in 90 % yield (Scheme ). The azide 9 underwent a further reduction/protection sequence to furnish the important compound 10 in 68 % yield …”

Section: Methodsmentioning

confidence: 99%

Organophotocatalytic Generation of N‐ and O‐Centred Radicals Enables Aerobic Oxyamination and Dioxygenation of Alkenes

Chen

et al. 2016

Chemistry A European J

119

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A cooperative TEMPO and photoredox catalytic strategy was applied for the first time to the direct conversion of N-H and O-H bonds into N- and O-centred radicals, enabling a general and selective oxidative radical oxyamination and dioxygenation of various β,γ-unsaturated hydrazones and oximes. In the reaction, O2 was employed not only as a terminal oxidant but also as the oxygen source. This protocol provided efficient access to the synthesis of various synthetically and biologically important pyrazoline, pyridazine and isoxazoline derivatives under metal-free and mild reaction conditions. Mechanistic studies revealed that the cooperative organophotocatalytic system functions through two single-electron-transfer (SET) processes.

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“…On the basis of the crystal structure of T. brucei CTPS glutaminase domain in complex with acivicin (PDB ID: 2W7T), different bromo‐acivicin derivatives, characterized by an increased molecular complexity, have also been synthesized with the aim to establish additional interactions with the binding pocket and, consequently, to enhance the affinity for the enzyme …”

Section: Antiparasitic Agentsmentioning

confidence: 99%

Inspired by Nature: The 3‐Halo‐4,5‐dihydroisoxazole Moiety as a Novel Molecular Warhead for the Design of Covalent Inhibitors

et al. 2015

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Over the past few decades, there has been an increasing interest in the development of covalent enzyme inhibitors. As it was recently re-emphasized, the selective, covalent binding of a drug to the desired target can increase efficiency and lower the inhibitor concentration required to achieve a therapeutic effect. In this context, the naturally occurring antibiotic acivicin, and in particular its 3-chloro-4,5-dihydroisoxazole scaffold, has provided a wealth of inspiration to medicinal chemists and chemical biologists alike. In this Concept, to underline the great potentiality that the 3-halo-4,5-dihydroisoxazole warhead has in drug discovery, we present a number of examples, grouped by their potential biological activity and targets, in which this scaffold has been fruitfully used to develop novel biologically active compounds. Through these examples, we show that the 3-halo-4,5-dihydroisoxazole moiety represents an outstanding warhead with high potential for the design of novel covalent enzyme inhibitors.

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Synthesis and Biological Evaluation of CTP Synthetase Inhibitors as Potential Agents for the Treatment of African Trypanosomiasis

Cited by 31 publications

References 25 publications

Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study

Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study

Organophotocatalytic Generation of N‐ and O‐Centred Radicals Enables Aerobic Oxyamination and Dioxygenation of Alkenes

Inspired by Nature: The 3‐Halo‐4,5‐dihydroisoxazole Moiety as a Novel Molecular Warhead for the Design of Covalent Inhibitors

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