Pharmacophore requirements for HIV-1 reverse transcriptase inhibitors that selectively “Freeze” the pre-translocated complex during the polymerization catalytic cycle

Lacbay, Cyrus M.; Menni, Michael; Bernatchez, Jean A.; Götte, Matthias; Tsantrizos, Youla S.

doi:10.1016/j.bmc.2018.02.017

Cited by 8 publications

(9 citation statements)

References 42 publications

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“…This class of compounds is known to have led to the discovery of Raltegravir (Figure ), the first in class HIV integrase inhibitor. Furthermore, in the antiviral field, the dihydroxypyrimidine core has been investigated to target other NA processing enzymes such as HIV-1 RT or HCV NS5B RNA-dependent RNA polymerase . Because of the close structural similarity between compound 4 and Raltegravir, a possible polypharmacology profile could be expected in the development of this class of compounds as NC inhibitors.…”

mentioning

confidence: 99%

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

Malancona

Mori

Fezzardi

et al. 2020

ACS Med. Chem. Lett.

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The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid 1 acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the 5-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound 28, showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.

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mentioning

confidence: 99%

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

Malancona

Mori

Fezzardi

et al. 2020

ACS Med. Chem. Lett.

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“…1,2,4-Oxadiazoles ( 13 and 15 ) were obtained using the following strategy: (1) acylation of corresponding amidoximes with activated carboxylic group of steroid compound 1 ; (2) cyclization of O -acylated amidoximes. The amidoximes (4-bromo- N’ -hydroxybenzimidamide and (2-(4-bromophenyl)- N ’-hydroxyacetimidamide) were synthesized according to the literature [ 27 ] from corresponding nitriles and hydroxylamine. Activation of the carboxyl group in compound 1 with CDI and subsequent reaction with amidoximes containing the para -bromophenyl moiety led to the formation of intermediates 12 and 14 with 77% and 80% yields, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…These compounds suppressed the TDP1 activity slightly better than the reference compound furamidine [30]. [27] from corresponding nitriles and hydroxylamine. Activation of the carboxyl group in compound 1 with CDI and subsequent reaction with amidoximes containing the para-bromophenyl moiety led to the formation of intermediates 12 and 14 with 77% and 80% yields, respectively.…”

Section: Inhibition Of Recombinant Enzymes Tdp1 and Tdp2mentioning

confidence: 86%

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New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2

et al. 2021

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A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para-bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC50 in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide 5 and para-bromoanilide 8 derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand 5 is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π–π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons.

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“…These small molecules acted as bioisosteres of pyrophosphate and provided a robust profile in the future designing of the impending therapeutics with potency to cure HIV infection (Lacbay et al, 2018).…”

Section: Pyrophosphate Mimics For the Inhibition Of Hiv‐1 Reverse Transcriptase Mediate Viral Replicationmentioning

confidence: 99%

Medicinal chemistry of pyrophosphate mimics: A mini review

Prasher

Sharma

2021

Drug Development Research

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The pyrophosphate mimicking groups offer rational modification of the pyrophosphate‐bearing natural substrates of the overexpressed enzymes that cause the onset of disease progression. Mainly, the modified substrate interacts differently with the enzyme active site eventually causing its deactivation, or provides the therapeutically active products at the completion of the catalytic cycle that contribute toward the inhibition of the target enzyme. Many of the pyrophosphate mimic‐containing molecules serve as competitive or allosteric inhibitors of the target enzyme to achieve the desirable properties for the mitigation of the target enzyme's pathophysiology. This review presents an epigrammatic overview of the pyrophosphate mimics in medicinal chemistry.

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Pharmacophore requirements for HIV-1 reverse transcriptase inhibitors that selectively “Freeze” the pre-translocated complex during the polymerization catalytic cycle

Cited by 8 publications

References 42 publications

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2

Medicinal chemistry of pyrophosphate mimics: A mini review

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