Iodine catalysed synthesis and antibacterial evaluation of thieno-[2,3-<i>d</i>]pyrimidine derivatives

Bakavoli, Mehdi; Bagherzade, Ghodsieh; Vaseghifar, Maryam; Shiri, Ali; Pordeli, Parvaneh

doi:10.3184/030823409x12537299044500

Cited by 16 publications

(11 citation statements)

References 29 publications

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“…16 . Briefly, 2-amino-4′,5′-disubstituted thiophene-3-carboxamide intermediates were obtained from condensation of the appropriate ketone and α-cyanoacetamide in the presence of elemental sulfur and base 17 .…”

Section: Resultsmentioning

confidence: 99%

Exploiting Drug-Resistant Enzymes as Tools To Identify Thienopyrimidinone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H

et al. 2013

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The thienopyrimidinone 5,6-dimethyl-2-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (DNTP) occupies the interface between the p66 ribonuclease H (RNase H) domain and p51 thumb of human immunodeficiency virus reverse transcriptase (HIV RT), thereby inducing a conformational change incompatible with catalysis. Here, we combined biochemical characterization of 39 DNTP derivatives with antiviral testing of selected compounds. In addition to wild-type HIV-1 RT, derivatives were evaluated with rationally-designed, p66/p51 heterodimers exhibiting high-level DNTP sensitivity or resistance. This strategy identified 3′,4′-dihydroxyphenyl (catechol)-substituted thienopyrimidinones with sub-micromolar in vitro activity against both wild type HIV-1 RT and drug-resistant variants. Thermal shift analysis indicates that, in contrast to active site RNase H inhibitors, these thienopyrimidinones destabilize the enzyme, in some instances reducing the Tm by 5°C. Importantly, catechol-containing thienopyrimidinones also inhibit HIV-1 replication in cells. Our data strengthens the case for allosteric inhibition of HIV RNase H activity, providing a platform for designing improved antagonists for use in combination antiviral therapy.

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Section: Resultsmentioning

confidence: 99%

Exploiting Drug-Resistant Enzymes as Tools To Identify Thienopyrimidinone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H

et al. 2013

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“…As reported in Scheme 1 , compounds 2 , 3, 6 − 13 , 15 − 21 were synthesised by a one-pot direct oxidative condensation of the appropriate commercially available 2-amino arylamide with the 3,4-disubstituted benzaldehyde in the presence of molecular iodine 46 . After 6 h, the reaction, carried out in acetonitrile at room temperature, afforded the final aryl pyrimidinone derivative in good yields.…”

Section: Resultsmentioning

confidence: 99%

Scaffold hopping and optimisation of 3’,4’-dihydroxyphenyl- containing thienopyrimidinones: synthesis of quinazolinone derivatives as novel allosteric inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H

Tocco

Esposito

Caboni

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Bioisosteric replacement and scaffold hopping are powerful strategies in drug design useful for rationally modifying a hit compound towards novel lead therapeutic agents. Recently, we reported a series of thienopyrimidinones that compromise dynamics at the p66/p51 HIV-1 reverse transcriptase (RT)-associated Ribonuclease H (RNase H) dimer interface, thereby allosterically interrupting catalysis by altering the active site geometry. Although they exhibited good submicromolar activity, the isosteric replacement of the thiophene ring, a potential toxicophore, is warranted. Thus, in this article, the most active 2-(3,4-dihydroxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3 H )-one 1 was selected as the hit scaffold and several isosteric substitutions of the thiophene ring were performed. A novel series of highly active RNase H allosteric quinazolinone inhibitors was thus obtained. To determine their target selectivity, they were tested against RT-associated RNA-dependent DNA polymerase (RDDP) and integrase (IN). Interestingly, none of the compounds were particularly active on (RDDP) but many displayed micromolar to submicromolar activity against IN.

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“…Regarding these points and as part of our ongoing studies dealing with the synthesis of various fused pyrimidines [28][29][30][31][32][33][34], herein, we wish to report on the synthesize of oxazolo [5,4-d] [1,2,4]triazolo [4,3-a]pyrimidine (5a-p) as members of a novel heterocyclic system that may be of use in designing new, potent and effective pharmacologically active compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidines as a New Class of Heterocyclic Compounds

Akbarzadeh

Bakavoli

Shiri

2015

Journal of Heterocyclic Chem

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Several new derivatives of oxazolo [5,4-d]pyrimidine (3a-h) have been synthesized through the reaction of 2,4-dichloro-6-methyl-5-nitropyrimidine (2) with aryl carboxylic acids in refluxing POCl 3 . Further treatment of compounds (3a-h) with hydrazine hydrate gave the hydrazine derivatives (4a-h) that were subsequently cyclized into a novel heterocyclic system, oxazolo [5,4-d][1,2,4]triazolo[4,3-a]pyrimidine (5a-p) and (7a-d) on treatment with triethylorthoesters or carbondisulfide and alkylhalides, respectively. H NMR (CDCl 3 ): δ 2.89 (s, 3H, CH 3 of pyrimidine), 7.45 (t, J = 7.4 Hz, 1H, 2-chlorophenyl), 7.53 (t, J = 7.4 Hz, 1H, 2-chlorophenyl), 7.58 (d, J = 8.0 Hz, 1H, 2-chlorophenyl), 8.14 (d, J = 7.6 Hz, 1H, 2-chlorophenyl); 13 C NMR (CDCl 3 ): δ 165.2, 162.7, 160.7, 155.2, 834

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Iodine catalysed synthesis and antibacterial evaluation of thieno-[2,3-d]pyrimidine derivatives

Cited by 16 publications

References 29 publications

Exploiting Drug-Resistant Enzymes as Tools To Identify Thienopyrimidinone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H

Exploiting Drug-Resistant Enzymes as Tools To Identify Thienopyrimidinone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H

Scaffold hopping and optimisation of 3’,4’-dihydroxyphenyl- containing thienopyrimidinones: synthesis of quinazolinone derivatives as novel allosteric inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H

Synthesis of Oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidines as a New Class of Heterocyclic Compounds

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