Rational design of novel diketoacid-containing ferrocene inhibitors of HIV-1 integrase

Silva, Carlos Henrique Tomich de Paula da; Ponte, Gino Del; Neto, Alberto Federman; Taft, Carlton A.

doi:10.1016/j.bioorg.2005.03.001

Cited by 20 publications

(41 citation statements)

References 11 publications

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“…Sagripanti and Lightfoote reported that ferric ions inactivate HIV when cells are infected with the virus and when the virus was free in solution (18). da Silva et al (19) and Nossik et al (20,21) have shown that ferrovir and ferrocene inhibit HIV replication. Our results are in agreement with the above studies, and taken together, suggest that iron based compounds may provide an effective complementary and alternative treatment for subjects infected with HIV virus.…”

Section: Discussionmentioning

confidence: 99%

“…Current research for the use of iron in the development of a new anti-AIDS drug is underway. Several compounds including iron ions with anti-HIV activity have been reported, such as ferrocene (Fe(II)(C 5 H 5 ) 2 ), an organometallic chemical compound (19), and ferrovir, a trivalent iron in complex with native sturgeon milt DNA (20,21). The present study was undertaken to investigate the in vitro anti-HIV activity of MRN-100, which is obtained from the plant extract phytosin.…”

Section: Introductionmentioning

confidence: 99%

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MRN‐100, An Iron‐Based Compound, Possesses Anti‐HIV Activity In Vitro

Ghoneum

Shaheen

2008

Evidence-Based Complementary and Alternative Medicine

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We examined the in vitro anti-human immunodeficiency virus (HIV) activity of MRN-100, an iron-based compound derived from bivalent and tervalent ferrates. MRN-100 action against HIV-1 (SF strain) was tested in primary cultures of peripheral blood mononuclear cells (MNC) by analyzing p24 antigen production and percent survival of MNC infected with HIV. MRN-100 at a concentration of 10% (v/v) inhibited HIV-1 replication in 11 out of 14 samples (79%). The percentage of suppression of p24 antigen was −12.3 to 100% at 10 days post-treatment. MRN-100 also exhibited a significant protective effect in the survival of HIV-1-infected MNC. MNC survival post-treatment was dose dependent, 70.4% ± 8.4, 83.6% ± 10.7 and 90% ± 11.4, at concentrations 2.5, 5 and 10% (v/v), respectively, as compared with 53% ± 4 for HIV-1-infected MNC without treatment. The effect was detected as early as 4 days and continued up to 11 days. Treatment with MRN-100 caused no significant change in proliferative response of MNC alone or cocultured with different mitogens: PHA and Con-A (activators of T cell function) and PWM (activator of CD4+ T cell-dependent B cells). We concluded that MRN-100 possesses anti-HIV activity in vitro and without an increase in lymphocyte proliferation, MRN-100 may be a useful agent for treating patients with acquired immunodeficiency syndrome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MRN‐100, An Iron‐Based Compound, Possesses Anti‐HIV Activity In Vitro

Ghoneum

Shaheen

2008

Evidence-Based Complementary and Alternative Medicine

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“…(14). Some other diketo acid-containing ferrocene inhibitors are also reported in the following molecular interaction field, density functional and docking studies [60]. Some other diketo acid-containing ferrocene inhibitors are also reported in the following molecular interaction field, density functional and docking studies [60].…”

Section: Diketo Acid-containing Ferrocenementioning

confidence: 90%

New Developments in Diketo-Containing Inhibitors of HIV-1 Integrase

Zhao

Wang²,

Liu³

et al. 2007

MRMC

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HIV-1 integrase is one of the three enzymes, which are critical for viral replication. It catalyzes the integration of the HIV genome into the cellular chromosome. Since there is no known human homolog to integrase, its inhibition is one of the most promising novel drug targets for anti-retroviral therapy with potential advantage over existing therapies. To date, numerous compounds with diverse structural features have been reported as integrase inhibitors, among which the diketo-containing inhibitors of HIV-1 integrase represent a major lead for anti-HIV drug development. The discovery of diketo acids plays an important role in validating integrase as a legitimate target for treatment of AIDS. In this review, we summarize several drug candidates in clinical trials and new diketo-containing inhibitors of HIV-1 integrase discovered recently.

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“…Docking was carried out using the X‐ray structure of PDE3B in complex with a dihydropyridazine inhibitor (1SO2.pdb) and PDE4B complexed with rolipram (1RO6). The ligands 12 , 13 , 14 , 15 , 19 , rolipram, and enoximone were built using the program HyperChem 8.0 and optimized using the density functional method, at the B3LYP/6‐31G* level , with the program Gaussian 09, revision A.02 (Gaussian Inc., Wallingford, CT, USA). The protein complex and the ligand were further prepared using the utilities implemented by AutoDockTools 1.5.4, revision 30 (http://mgltools.scripps.edu/).…”

Section: Methodsmentioning

confidence: 99%

Ferrocenyl, Alkyl, and Aryl‐Pyrido[2,3‐d]Pyrimidines as Vasorelaxant of Smooth Muscle of Rat Aorta via cAMP Conservation Through Phosphodiesterase Inhibition

Arellano

Rodríguez-Ramos

González-Andrade

et al. 2015

Journal of Heterocyclic Chem

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in Wiley Online Library (wileyonlinelibrary.com).New pyrido [2,3-d]pyrimidines 11, 12, 13, and 21 have been synthesized. The vasorelaxant effect on smooth muscle isolated from rat aorta, via PDEs inhibition, of these compounds along with other pyrido [2,3-d]pyrimidines 14-20 reported earlier by our group, has also been determined. These pyrido[2,3-d]pyrimidines 11-21 were synthesized by the reaction of ferrocenyl-ethynyl ketones (1-4) or α-alkynyl ketones (5-10) with 6-amino-1,3-dimethyluracil using [Ni(CN) 4 ] À4 as an active catalytic species, formed in situ in a Ni(CN) 2 /NaOH/H 2 O/CO/KCN aqueous system. Evaluation of the vasorelaxant effect of compounds 11-21 demonstrated that all compounds relax the tissue in a concentration-dependent manner. The structural changes do not alter the effectiveness; however, there are differences related to potency expressed as EC 50 . Compounds 12 (7-ferrocenyl-1,3-dimethyl-5-(m-tolyl)-pyrido[2,3-d]pyrimidine) and 13 (7ferrocenyl-1,3-dipropyl-5-(4-metoxyphenyl)-pyrido[2,3-d]pyrimidine) were the most potent compounds, even more than rolipram, reference drug; the EC 50 was 0.41 ± 0.02 μM and 0.81 ± 0.11 μM for 12 and 13, correspondingly. The EC 50 of compounds 15 (7-ferrocenyl-1,3-dimethyl-5-phenyl-pyrido[2,3-d]pyrimidine), 14 (7-ferrocenyl-5-(3,5-dimethoxyphenyl)-1,3-dimethylpyrido[2,3-d]pyrimidine), and 19 (5-n-butyl-7-ethyl-1,3-dimethylpyrido[2,3-d]pyrimidine) was similar to EC 50 of rolipram. Compounds 11-21 significantly induce concentration-dependent vasorelaxation in endothelium-intact aortic rings. In addition, the relaxation responses to each compound in either endothelium-intact or endothelium denuded aortic rings were comparable, suggesting that removal of the functional endothelium has no significant influence on its intrinsic vasorelaxant activity. In vitro capability of conserving cyclic-AMP or cyclic-GMP (adenosine and guanosine 3′, 5′-cyclic monophosphate) via PDE inhibition for compounds 12-15 and 19 was evaluated. Compounds 15 and 19 show the highest percent inhibition effect (94.83% and 83.98%, respectively) for the decomposition of c-AMP. Docking studies showed that the compound 15 was selective for the inhibition of PDE-4.

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Rational design of novel diketoacid-containing ferrocene inhibitors of HIV-1 integrase

Cited by 20 publications

References 11 publications

MRN‐100, An Iron‐Based Compound, Possesses Anti‐HIV Activity In Vitro

MRN‐100, An Iron‐Based Compound, Possesses Anti‐HIV Activity In Vitro

New Developments in Diketo-Containing Inhibitors of HIV-1 Integrase

Ferrocenyl, Alkyl, and Aryl‐Pyrido[2,3‐d]Pyrimidines as Vasorelaxant of Smooth Muscle of Rat Aorta via cAMP Conservation Through Phosphodiesterase Inhibition

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