Synthesis and Anti-Human Immunodeficiency Virus Type 1 Integrase Activity of Hydroxybenzoic and Hydroxycinnamic Acid Flavon-3-yl Esters

Desideri, N.; Sestili, Isabella; Stein, M. L.; Tramontano, Enzo; Corrias, S.; Colla, Paolo La

doi:10.1177/095632029800900606

Cited by 16 publications

(9 citation statements)

References 46 publications

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“…Among them, II-25 was the most promising compound and exhibited potent inhibitory activity against HIV-1 RNase H, with an IC 50 value of 0.72 ± 0.07 μM, 2.8 times more potent than β-thujaplicinol in enzymatic assays. Interestingly, II-25 and other tested galloyl derivatives were also found to inhibit the HIV IN strand transfer activity, a property shared by related compounds such as gallic acid flavon-3-yl esters (Desideri et al, 1998). Unfortunately, the designed compounds fail to exhibit significant inhibitory activity in infected cells, probably due in part to their poor permeability through the cell membrane.…”

Section: Discussionmentioning

confidence: 99%

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV‐1 RNase H inhibitors

et al. 2019

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Human immunodeficiency virus (HIV) reverse transcriptase (RT)‐associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not targeted by current antiviral drugs. In this work, we report the design, synthesis, and biologic evaluation of a novel series of galloyl derivatives with HIV‐1 RNase H inhibitory activity. Most of them showed IC50s at sub‐ to low‐micromolar concentrations in enzymatic assays. The most potent compound was II‐25 that showed an IC50 of 0.72 ± 0.07 μM in RNase H inhibition assays carried out with the HIV‐1BH10 RT. II‐25 was 2.8 times more potent than β‐thujaplicinol in these assays. Interestingly, II‐25 and other galloyl derivatives were also found to inhibit the HIV IN strand transfer activity in vitro. Structure–activity relationships (SAR) studies and molecular modeling analysis predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization of selected compounds.

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Section: Discussionmentioning

confidence: 99%

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV‐1 RNase H inhibitors

et al. 2019

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“…Compounds were synthesized as described (Desideri et al, 1998). Stock solutions were prepared in ethanol (1 or 0.1 mg/ml) and further diluted in tissue culture medium shortly before use.…”

Section: Compoundsmentioning

confidence: 99%

Anti-Picornavirus Activity of Synthetic Flavon-3-yl Esters

Conti

Mastromarino

Sgro

et al. 1998

Antivir Chem Chemother

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Members of the family Picornaviridae, which comprise rhinoviruses and enteroviruses, are responsible for several human diseases. It is estimated that over 100 serotypes of human rhinoviruses (HRV) cause approximately half of all cases of the common cold. Also, poliomyelitis still represents a relevant health problem in some countries of the world, despite a dramatic decrease in its incidence as a result of intensive vaccination programmes in developed countries. There therefore exists a need to search for effective chemotherapeutic agents for picornavirus infections.Several classes of flavonoids, isolated from plants utilized in traditional medicine, possess a well recognized anti-picornavirus activity (Van Hoof et al.,1984;Kaul et al., 1985;Tsuchiya et al., 1985). Among polyhydroxylated flavones, quercetin was originally described to reduce the infectivity and the intracellular replication of poliovirus type 1 (PV-1), but not of PV-2 or PV-3. Hesperetin, a flavanone, was able to interfere with PV-1 infection of cell monolayers without affecting virus infectivity (Kaul et al., 1985). 3-Methoxylated flavones, such as chrysosplenol B and C, and axillarin, were found to have potent anti-HRV activity, whereas flavones without a methoxyl group at the 3-position had no anti-rhinovirus activity (Tsuchiya et al., 1985). Beside an effect on HRVs, 4′,5-dihydroxy-3,3′,7-trimethoxyflavone (Ro-09-0179) also exerted an inhibitory activity against coxsackieviruses in tissue cultures (Kaul et al., 1985). The mechanism of action of flavonoids has been attributed to interference with an early stage of viral infection, probably represented by viral RNA synthesis (Castrillo et al., 1986;Gonzales et al., 1990).The study of various synthetic flavones, structurally related to natural flavonoids, confirmed the anti-picornavirus activity of this class of compounds (De Meyer et al., 1991;Desideri et al., 1995). Among the derivatives studied by us, flavanones were generally less effective against picornaviruses than flavones, and 3-hydroxy or 3-methoxyflavones were more active than 3-unsubstituted flavones. The presence of a 3-hydroxy group increased the anti-PV potency, whereas a 3-methoxy group enhanced the effect against HRV-1B ( Desideri et al., 1995). In order to further study the influence on anti-picornavirus activity of the substituent in position 3 of synthetic flavones, we extended our research to esters of chloroflavon-3-ols with natural occurring hydroxybenzoic and hydroxycinnamic acids, i.e. gallic, syringic, caffeic, vanillic and ferulic acids (compounds 2 a-h, 3 a-l). Materials and Methods: VirologyCells HeLa (Ohio) cells were routinely grown at 37°C in 75 cm 2 tissue culture flasks using Eagle's MEM supplemented with 100 µg/ml of streptomycin and 100 U/ml of penicillin G. Eight percent heat-inactivated fetal calf serum (FCS) was added for cell growth (growth medium); the concentration was reduced to 2% for cell maintenance (maintenance medium). The in vitro antiviral activity against picornaviruses (rhinovirus serotype 1B ...

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“…Flavones as quercetin, for instance, lack antiviral activity and, in addition to IN, inhibit several other viral and cellular enzymes [125][126][127][128]. On the other hand, biscatechols like β-conidendrol and hematoxylin, although specifically inhibiting rIN, lack antiviral activity [129].…”

Section: Hydroxylated Aromaticsmentioning

confidence: 97%

“…On the other hand, biscatechols like β-conidendrol and hematoxylin, although specifically inhibiting rIN, lack antiviral activity [129]. The group of hydroxylated aromatics which display anti-HIV activity in cell-based assays includes ATA [87,88,130], cosalane [88], curcumin [131], bis-coumarins [132], some CAPE-derivatives [76,89,123,125], anthraquinones [21,73,94], DCQAs and LCH [91,92,133]. Some of these inhibitors, however, target steps of the HIV life cycle other than integration.…”

Section: Hydroxylated Aromaticsmentioning

confidence: 99%

Anti-HIV-1 Integrase Drugs How Far from the Shelf

Pani

Marongiu²

2000

CPD

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Chemotherapy of HIV-1 infection/AIDS currently employs inhibitors of two products of the viral pol gene, the reverse transcriptase and protease enzymes. However, a third product of the pol gene is essential for retroviral multiplication, the integrase. As no cellular homologue of HIV integrase has been described, potential inhibitors could be relatively nontoxic. Development of HIV-1 integrase inhibitors could have favorable implication for combination therapy, including potential synergy with currently available inhibitors, as well as prevention of the chronic carrier state and the emergence of resistant mutants. Although several classes of putative integrase inhibitors that been described, still no clinically useful anti-integration drugs are available. It is the structural and functional complexity of the integration process together with the limitations of the available in vitro assays that has made it problematic to develop inhibitors of the HIV integrase. In this review we summarize current knowledge concerning the biology of this enzyme and of the integration process, and discuss major classes representatives of integrase inhibitors considering the obstacles to the development of true anti-integrase drugs.

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Synthesis and Anti-Human Immunodeficiency Virus Type 1 Integrase Activity of Hydroxybenzoic and Hydroxycinnamic Acid Flavon-3-yl Esters

Cited by 16 publications

References 46 publications

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV‐1 RNase H inhibitors

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV‐1 RNase H inhibitors

Anti-Picornavirus Activity of Synthetic Flavon-3-yl Esters

Anti-HIV-1 Integrase Drugs How Far from the Shelf

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