New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3′,3′-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 μM and 0.03 μM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.

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Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study

Biomolecules ◽

10.3390/biom10081148 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1148

Author(s):

Krzysztof Marciniec ◽

Elwira Chrobak ◽

Aleksandra Dąbrowska ◽

Ewa Bębenek ◽

Monika Kadela-Tomanek ◽

...

Keyword(s):

Molecular Docking ◽

Betulinic Acid ◽

Strong Interactions ◽

Molecular Docking Study ◽

Gag Protein ◽

Terminal Domain ◽

Derivatives Of ◽

Anti Hiv ◽

Hiv 1

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3–5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3′,3′-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.

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Benzothiazol Clubbed Imidazol-4-ones as Anti-fungal, Anti-tubercular and Anti-HIV-1 Agents: Their Synthesis and Molecular Docking Study

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180712150050 ◽

2019 ◽

Vol 16 (4) ◽

pp. 382-391

Author(s):

Navin B. Patel ◽

Asif R. Shaikh ◽

Vatsal M. Patel ◽

Edgar E. Lara-Ramirez ◽

Gildardo Rivera

Keyword(s):

Molecular Docking ◽

Reverse Transcriptase ◽

Docking Study ◽

Antimicrobial Activities ◽

Spectral Studies ◽

Molecular Docking Study ◽

Broth Microdilution Method ◽

Anti Hiv ◽

Hiv 1

Background: The present work describes antimicrobial, antimycobacterium and anti HIV-1 evaluation of newly synthesized 5-(4-Substituted-benzylidene)-3-[4-(5-methyl-benzothiazol- 2-yl)-phenyl]-2-phenyl-3,5-dihydro-imidazol-4-one (4a-o). The docking studies were performed in order to predict the potential binding affinities. Objective: The major aim of this study is to develop the new class of bezylidine candidate clubbed with benzothiazole with less toxicity and improved potency as antimicrobial, antitubercular and anti HIV-1. Methods: The titled compounds were characterized by spectral studies (IR, 1H NMR, 13C NMR and Mass). In vitro antimycobacterium activity was carried out using Lowenstein-Jensen medium method and antimicrobial activity using the broth microdilution method. The anti HIV-1 reverse transcriptase activity was determined by the colorimetric MTT method and inhibition of virusinduced cytopathogenicity in MT-4 cells. Results: Compound 4i (50 µM) showed better antifungal activity against A. clavatus. Compound 4g (50 µM) with 95% inhibition demonstrated good activity against M. tuberculosis H37Rv. Compound 4k showed CC50 (50 µM) against MT-4 (CD4+ Human T-cells containing an integrated HTLV-1 genome) cells by 50%, while 16 µM concentration value EC50 from the HIV-1 induced cytopathogenicity. Molecular docking study suggested that 4k interacted with the target with binding energy by Vina score (-10.3 Kcal/mol). Conclusion: The preliminary in vitro evaluation results revealed that some of the compounds have promising antimicrobial activities as well as antitubercular potency. Among the various substituents on benzylidene, the nitro group was the most beneficial for improving the anti-HIV-1 activity. Docking result suggested that 4k compound could be acting as a non-competitive or weak inhibitor of Reverse Transcriptase (RT).

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Anti-HIV-1 Integrase Activity and Molecular Docking Study of Compounds from Caesalpinia sappan L.

Phytotherapy Research ◽

10.1002/ptr.5307 ◽

2015 ◽

Vol 29 (5) ◽

pp. 724-729 ◽

Cited By ~ 9

Author(s):

Supinya Tewtrakul ◽

Prapaporn Chaniad ◽

Somsak Pianwanit ◽

Chatchanok Karalai ◽

Chanita Ponglimanont ◽

...

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Molecular Docking Study ◽

Caesalpinia Sappan ◽

Anti Hiv ◽

Hiv 1

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Synthesis and Molecular Docking Study of Novel Chromeno-chromenones as Anti-HIV-1 NNRT Inhibitors

Synlett ◽

10.1055/s-0034-1381043 ◽

2015 ◽

Vol 26 (14) ◽

pp. 1969-1972 ◽

Cited By ~ 5

Author(s):

Sudhakar Bhusare ◽

Hanmant Kasralikar ◽

Suresh Jadhavar

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Molecular Docking Study ◽

Anti Hiv ◽

Hiv 1

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Rational in silico drug design of HIV-RT inhibitors through G-QSAR and molecular docking study of 4-arylthio and 4-aryloxy-3-iodopyridine-2(1-H)-one derivative

Beni-Suef University Journal of Basic and Applied Sciences ◽

10.1186/s43088-020-00075-7 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Debadash Panigrahi ◽

Amiyakanta Mishra ◽

Susanta Kumar Sahu

Keyword(s):

Molecular Docking ◽

Reverse Transcriptase ◽

Active Site ◽

Docking Study ◽

Molecular Docking Study ◽

Immunodeficiency Virus ◽

Qsar Models ◽

Hiv Rt ◽

Rt Inhibitors ◽

Anti Hiv

Abstract Background Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Antiretroviral therapy (ART) against HIV infection offers the promise of controlling disease progression and prolonging the survival of HIV-infected patients. Reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In this direction, by using group-based QSAR study (G-QSAR), identification of the structural need for the development of lead structure with reverse transcriptase inhibition on 97 reported structures was carried out. Docking analysis was performed further and suggested the structural properties required for binding affinity with the receptor. The molecules in the data set were fragmented into six (R1, R2, R3, R4, R5, and R6) by applying the fragmentation pattern. Three G-QSAR models were selected based on the statistical significance of the model. The molecular docking study was performed to explain the structural properties required for the design of potent HIV-RT inhibitors. Results The statistically validated QSAR models reveal the presence of higher hydrophobic groups containing single-bonded –Br atom, 2 aromatic bonded –NH group with less electronegativity, and entropic interaction fields at R2 essential for better anti-HIV activity. The presence of a lipophilic group at R3, oxygen and sulfur connected with two aromatic bonds at R4, and –CH3 group at R5 was fruitful for reverse transcriptase inhibition. Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond, Van der Waal’s, charge, aromatic, and π–π interactions with residues present at the active site. Conclusion The results of the generated models provide significant site-specific insight into the structural requirements for reverse transcriptase inhibition during the design and development of novel anti-HIV compounds. Molecular docking study revealed the binding interaction between the ligand and the receptor which gave insight towards the structure-based design for the discovery of more potent compounds with better activity against HIV infection.

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Anti-HIV-1 integrase effect of compounds fromAglaia andamanicaleaves and molecular docking study with acute toxicity test in mice

Pharmaceutical Biology ◽

10.3109/13880209.2015.1071413 ◽

2015 ◽

Vol 54 (4) ◽

pp. 654-659 ◽

Cited By ~ 2

Author(s):

Jindaporn Puripattanavong ◽

Pattreeya Tungcharoen ◽

Prapaporn Chaniad ◽

Somsak Pianwanit ◽

Supinya Tewtrakul

Keyword(s):

Molecular Docking ◽

Acute Toxicity ◽

Toxicity Test ◽

Docking Study ◽

Acute Toxicity Test ◽

Molecular Docking Study ◽

Anti Hiv ◽

Hiv 1

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Anti-HIV-1 integrase compounds fromDioscorea bulbiferaand molecular docking study

Pharmaceutical Biology ◽

10.3109/13880209.2015.1103272 ◽

2016 ◽

Vol 54 (6) ◽

pp. 1077-1085 ◽

Cited By ~ 13

Author(s):

Prapaporn Chaniad ◽

Chatchai Wattanapiromsakul ◽

Somsak Pianwanit ◽

Supinya Tewtrakul

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Molecular Docking Study ◽

Anti Hiv ◽

Hiv 1

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ChemInform Abstract: Synthesis and Molecular Docking Study of Novel Chromeno-Chromenones as anti-HIV-1 NNRT Inhibitors.

ChemInform ◽

10.1002/chin.201603141 ◽

2016 ◽

Vol 47 (3) ◽

Author(s):

Hanmant M. Kasralikar ◽

Suresh C. Jadhavar ◽

Sudhakar R. Bhusare

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Molecular Docking Study ◽

Anti Hiv ◽

Hiv 1

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Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

Medicinal Chemistry ◽

10.2174/1573406415666190724142951 ◽

2020 ◽

Vol 16 (7) ◽

pp. 892-902 ◽

Cited By ~ 3

Author(s):

Aida Iraji ◽

Mahsima Khoshneviszadeh ◽

Pegah Bakhshizadeh ◽

Najmeh Edraki ◽

Mehdi Khoshneviszadeh

Keyword(s):

Molecular Docking ◽

Active Site ◽

Competitive Inhibition ◽

Docking Study ◽

Biological Evaluation ◽

Primary Response ◽

Ratio Method ◽

Molecular Docking Study ◽

Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti– tyrosinase agents. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

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