- Conformational Features of Thioamide-Containing Dipeptoids and Peptoid-Peptide Hybrids - Computational and Experimental Approaches
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The effects of thioamide incorporation into N,N-dimethyl-2-(N-methylacetamido)acetamide and N-methyl-2-(N-methylacetamido)acetamide as the simplest models of a dipeptoid structure and a peptoid-peptide hybrid are discussed. The solvent-modulated conformational features of model compounds were examined by computations enhanced by natural bond orbital (NBO) analysis and experimentally by kinetic and equilibrium measurements using NMR spectroscopy. The computations supported by NBO analysis showed that intrinsic stability of the predominant trans isomer (αD and C7β forms) of the dipeptoid model results from an indirect n → π? interaction, occurring between the carbonyl oxygen lone pair (n) and the π? orbital of the adjacent amide carbonyl through the C-H antibond (σ?). The direct n → π? interaction constitutes a negligible contribution to trans stabilization. The N-terminal thioxo substitution increases this indirect electron delocalization, making the αD isomer prevalent. The nX → σN′C-H? interaction is an additional source of stability of the trans-C7β form relevant for the underivatized dipeptoid model and its C-terminal thioamide counterpart. In the peptoid-peptide hybrid, the trans preference is perturbed by subtle differences in the H-bond donor-acceptor abilities between the thioxo and oxo groups. The cis isomer becomes more populated with an increase in the strength of polarity and the hydrogen bonding acceptor ability of the solvent molecules. While thioxo substitution slightly shifts the trans-cis equilibrium in polar solvents, it effectively allows for increasing or decreasing the barrier to trans-cis rotation with respect to underivatized model compounds depending on N- vs C-terminal thioamide backbone substitution.
- Zimnicka, Magdalena M.
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- The structure-activity profile of mercaptobenzamides’ anti-HIV activity suggests that thermodynamics of metabolism is more important than binding affinity to the target
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Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed. Finally, using NMR-derived thiol–thioester exchange equilibrium constants, we propose that thermodynamics plays a role in determining the antiviral activity observed in the SAR profile.
- Nikolayevskiy, Herman,Robello, Marco,Scerba, Michael T.,Pasternak, Evan H.,Saha, Mrinmoy,Hartman, Tracy L.,Buchholz, Caitlin A.,Buckheit, Robert W.,Durell, Stewart R.,Appella, Daniel H.
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p. 818 - 837
(2019/06/27)
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- Microwave-assisted solvent-free intramolecular 1,3-dipolar cycloaddition reactions leading to hexahydrochromeno[4,3-b]pyrroles: scope and limitations
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We report the microwave-assisted solvent-free synthesis of hexahydrochromeno[4,3-b]pyrroles. Intramolecular 1,3-dipolar cycloadditions proceed under these conditions within 15-40 min in 16-84% yields. An influence of the microwave irradiation upon various [3+2] cycloaddition reaction intermediates was studied. Additionally, a scope and limitations of these reactions including an influence of the dipolarophile geometry upon the cycloaddition selectivity and steric demands of the dipole upon its reactivity were also disclosed. These observations led us to postulate a preferable transition state of the reaction. Finally, an influence of the microwave irradiation to the isomerization of activated olefins was also described.
- Pospí?il, Ji?í,Potá?ek, Milan
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p. 337 - 346
(2007/10/03)
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- 2-Substituted Penems with Amino Acid-Related Side Chains: Synthesis and Antibacterial Activity of a New Series of β-Lactam Antibiotics
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A new series of 6-(hydroxyethyl)penems 2-substituted with amino acid-related side chains was synthesized.The nature of the amino acyl derivative proved to be crucial both from a synthetic point of view, as β-lactam ring opening can compete with C-2 nucleophilic substitution, and for antibacterial activity.Primary amino acid amides emerged as the most suitable side chains for enhancing permeability through a Gram-negative outer membrane.In vitro activity of the new 2-penems 3a-u was influenced by the nature and position of the amide moiety, the ring size for cyclic amides, and the configuration of the amino acid.Compounds bearing amides derived from small N-methyl amino acids (such as 3a) or from cyclic amino acids (such as prolinamide 3p and 4-hydroxyprolinamide 3r) showed broad spectrum in vitro activity against both Gram-positive and Gram-negative microorganisms.
- Altamura, Maria,Perrotta, Enzo,Sbraci, Piero,Pestellini, Vittorio,Arcamone, Federico,et al.
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p. 4244 - 4256
(2007/10/03)
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