Zidovudine: Structural Modifications and Their Impact on Biological Activities and Pharmacokinetic Properties

Mohsin, Noor ul Amin; Ahmed, Matloob; Irfan, Muhammad

doi:10.4067/s0717-97072019000304523

Cited by 5 publications

(3 citation statements)

References 45 publications

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“…1 Some studies on structural modifications of zidovudine (AZT) have shown that the 5′-OH group can be modified with better antiviral potency, pharmacokinetic properties, and cytoprotective properties. 6 Therefore, it was envisaged that new approaches could be adopted for antiretroviral agents (ARAs) with antioxidants (AO) (Figure 1). In this Viewpoint, we primarily assume an approach to make ARA−AO conjugates and in silico calculations have shown an increase of log p values and molecular weight (critical factors for CNS penetration and distribution).…”

Section: Clinical Status Of Antiretroviral Agents In the Treatment Of...mentioning

confidence: 99%

“…Clinical studies have reported that antiretroviral therapy (ART) in HAND has limitations due to poor CNS penetration and hence a lower concentration is maintained in the CSF to inhibit the viral replication and is found to be not very effective . Some studies on structural modifications of zidovudine (AZT) have shown that the 5′-OH group can be modified with better antiviral potency, pharmacokinetic properties, and cytoprotective properties . Therefore, it was envisaged that new approaches could be adopted for antiretroviral agents (ARAs) with antioxidants (AO) (Figure ).…”

Section: Clinical Status Of Antiretroviral Agents In the Treatment Of...mentioning

confidence: 99%

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Investigation of Molecular Properties of Antiretroviral Agents to Enhance CNS Penetration Abilities for the Treatment of Cognitive Impairment in HIV-Associated Neurocognitive Disorder

Danta

Piplani

2020

ACS Chem. Neurosci.

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HIV-associated neurocognitive disorder (HAND) can be represented by neurological and neuropathological abnormalities with a consequence of motor and cognitive loss. It has become a critical unmet medical need for infected people, and the number continues to rise every year. Pathological investigations have revealed its occurrence due to the release of free radicals from the HIV infected microglia and macrophages. So far, no effective clinical trials have been conducted for its treatment other than the use of some antiretroviral therapies which have failed to show good results due to poor CNS penetration and hence low CNS distribution. This collective information from the updated literature reports motivated us to share the idea of conjugated products of antiretroviral agents and antioxidants leading to better brain penetration abilities due to higher log p values, higher molecular weight and possibly low toxicity and better neuroprotective action. In this Viewpoint, we have attempted to analyze the chemical and pharmacological classes of antiretroviral agents (ARAs) and their clinical failures for the treatment of cognitive dysfunction due to HIV infection. As the causes of clinical insufficiency of antiretroviral agents and neuropathological mechanisms of HAND have been well established, it would be a good opportunity for medicinal chemists to develop new potential antiretroviral agents or to improve their molecular properties for better therapeutic implications. Furthermore, in silico based molecular properties have been investigated correlating them to the brain penetration abilities.

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Section: Clinical Status Of Antiretroviral Agents In the Treatment Of...mentioning

confidence: 99%

Section: Clinical Status Of Antiretroviral Agents In the Treatment Of...mentioning

confidence: 99%

Investigation of Molecular Properties of Antiretroviral Agents to Enhance CNS Penetration Abilities for the Treatment of Cognitive Impairment in HIV-Associated Neurocognitive Disorder

Danta

Piplani

2020

ACS Chem. Neurosci.

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“…An important trend in the chemotherapy field involves the study of nucleoside analogs and the analysis of their multiple antioxidant, antitumor, antimicrobial, and antiviral properties [ 34 , 35 , 36 , 37 ]. Azidothymidine (AZT), also known as zidovudine (ZDV), is a synthetic nucleoside analog of thymidine that was originally synthesized as an antitumor compound but gained notable prominence due to its inhibitory activity on reverse transcriptase, an essential enzyme for HIV replication [ 38 , 39 ]. Interestingly, current studies have revealed that AZT has also been described as an inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) in vitro (kinetic test) [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

Antiviral Effect of 5′-Arylchalcogeno-3-aminothymidine Derivatives in SARS-CoV-2 Infection

Tucci,

da Rosa,

Rosa

et al. 2023

Molecules

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The understanding that zidovudine (ZDV or azidothymidine, AZT) inhibits the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and that chalcogen atoms can increase the bioactivity and reduce the toxicity of AZT has directed our search for the discovery of novel potential anti-coronavirus compounds. Here, the antiviral activity of selenium and tellurium containing AZT derivatives in human type II pneumocytes cell model (Calu-3) and monkey kidney cells (Vero E6) infected with SARS-CoV-2, and their toxic effects on these cells, was evaluated. Cell viability analysis revealed that organoselenium (R3a–R3e) showed lower cytotoxicity than organotellurium (R3f, R3n–R3q), with CC50 ≥ 100 µM. The R3b and R3e were particularly noteworthy for inhibiting viral replication in both cell models and showed better selectivity index. In Vero E6, the EC50 values for R3b and R3e were 2.97 ± 0.62 µM and 1.99 ± 0.42 µM, respectively, while in Calu-3, concentrations of 3.82 ± 1.42 µM and 1.92 ± 0.43 µM (24 h treatment) and 1.33 ± 0.35 µM and 2.31 ± 0.54 µM (48 h) were observed, respectively. The molecular docking calculations were carried out to main protease (Mpro), papain-like protease (PLpro), and RdRp following non-competitive, competitive, and allosteric inhibitory approaches. The in silico results suggested that the organoselenium is a potential non-competitive inhibitor of RdRp, interacting in the allosteric cavity located in the palm region. Overall, the cell-based results indicated that the chalcogen-zidovudine derivatives were more potent than AZT in inhibiting SARS-CoV-2 replication and that the compounds R3b and R3e play an important inhibitory role, expanding the knowledge about the promising therapeutic capacity of organoselenium against COVID-19.

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Fluorocyclization of Vinyl Azides for the Formation of 3‐Azido Heterocycles

Dian-gang

et al. 2020

Chemistry An Asian Journal

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3-Azido saturated heterocycles are important for therapeutic-development but challenging to prepare. Disclosed herein is a novel synthetic strategy for 3-azido heterocycles via fluorocyclization of the easily available vinyl azides. This transformation proceeded under mild conditions and provided a wide range of 3-azido heterocycles in good to excellent yields. Notably, the azido group plays an indispensable role to promote rapid and regioselective fluorocyclization. Moreover, the protocol was highlighted by gram-scale synthesis and further synthetic transformations.

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Zidovudine: Structural Modifications and Their Impact on Biological Activities and Pharmacokinetic Properties

Cited by 5 publications

References 45 publications

Investigation of Molecular Properties of Antiretroviral Agents to Enhance CNS Penetration Abilities for the Treatment of Cognitive Impairment in HIV-Associated Neurocognitive Disorder

Investigation of Molecular Properties of Antiretroviral Agents to Enhance CNS Penetration Abilities for the Treatment of Cognitive Impairment in HIV-Associated Neurocognitive Disorder

Antiviral Effect of 5′-Arylchalcogeno-3-aminothymidine Derivatives in SARS-CoV-2 Infection

Fluorocyclization of Vinyl Azides for the Formation of 3‐Azido Heterocycles

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