Synthesis, Molecular Modelling and Biological Studies of 3-hydroxypyrane- 4-one and 3-hydroxy-pyridine-4-one Derivatives as HIV-1 Integrase Inhibitors

Sirous, Hajar; Fassihi, Afshin; Brogi, Simone; Campiani, Giuseppe; Christ, Frauke; Debyser, Zeger; Butini, Stefania; Chemi, Giulia; Grillo, Alessandro; Zabihollahi, Rezvan; Aghasadeghi, Mohammad Reza; Saghaie, Lotfollah; Memarian, Hamid Reza

doi:10.2174/1573406415666181219113225

Cited by 21 publications

(28 citation statements)

References 75 publications

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“…Computational studies were conducted using our recently described theoretical model of full-length HIV-1 IN in complex with viral DNA and Mg 2+ cofactors (Sirous et al, 2019). The model was subjected to Protein Preparation Wizard protocol implemented in Maestro.…”

Section: Methodsmentioning

confidence: 99%

“…Accordingly, HP derivatives represent an impressive class of heterocyclic ligands with strong bidentate chelating capacity toward metal ions (Santos et al, 2012; Rostami et al, 2015; Sirous et al, 2015). As a first example of the potential of this structural template in HIV-IN inhibition, a series of HP compounds featuring a unique C-2 carboxamide moiety, namely 3-hydroxyl-pyran-4-one-2-carboxamide derivatives (HPCARs), were rationally designed and recently reported by us (Figure 2; Sirous et al, 2019). The proposed chemotypes were characterized by a chelating triad motif effectively coordinating the two metals according to the pharmacophore shared by INIs.…”

Section: Introductionmentioning

confidence: 99%

“…Most of these HPCAR analogs offered favorable inhibitory potencies in both enzymatic and cell-based antiviral assays with low micromolar IC 50 values. In particular, the substitution at the para position of the aromatic phenyl ring led to the identification of two halo-benzyl derivatives HPb and HPd (Figure 2) as promising lead HIV-1 IN inhibitors with IC 50 values of 0.37 and 0.7 μM, respectively (Sirous et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

et al. 2019

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We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an in silico structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed in vitro for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the in vitro tests along with no toxicity. Among them HPCAR-28 represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline HPCAR-28 as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

et al. 2019

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“…Homology modeling of bovine arginase. The homology model of B-ARG was generated by following a computational protocol described by us [40,41]. The sequence of B-ARG was taken in FASTA format from UniProtKB (entry Q2KJ64).…”

Section: Computational Detailsmentioning

confidence: 99%

Cinnamides Target Leishmania amazonensis Arginase Selectively

et al. 2020

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Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3–17.8 μM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors.

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“…For the molecules possessing known stereochemistry, the absolute configuration was specified during the drawing of the compounds. All structures were treated by LigPrep module of Schrödinger suite 2015 [94] in order to generate the most probable ionization state at the cellular pH value (7.4 ± 0.2) as reported by us [95][96][97]. Moreover, the OPLS-AA_2005 force field was used for optimization, which produces the lowest energy conformer of the ligand [98].…”

Section: Ligands and Data Set Preparationmentioning

confidence: 99%

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

et al. 2020

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Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R 2 = 0.958) and a satisfactory predictive power (Q 2 = 0.822; Q 2 F3 = 0.894). The model was validated (r 2 ext_ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner-Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity.Molecules 2020, 25, 1952 2 of 20 chromatin structure which concomitantly restricts the accessibility of related transcriptional factors to their target genes, thereby suppressing gene expression including tumor suppressor genes [6][7][8]. The abnormal regulation of this process culminates with the high expression level of HDACs. This event has been observed in the development of several human cancers. Consequently, effective inhibition of HDACs has recently gained importance as a valid therapeutic strategy to reverse aberrant epigenetic changes associated with cancer [9][10][11]. HDAC inhibitors (HDACIs) induce histone hyperacetylation and subsequent transcriptional re-activation of suppressed genes which are correlated with a variety of effects on tumor cells including apoptosis, differentiation, cell cycle arrest, inhibition of proliferation and cytostasis [12,13].The HDAC family comprises 18 isoforms in mammalian cells which are categorized into four main classes (class I-IV) based on their structural and functional characteristics. HDACs belonging to class I (HDAC1-3 and 8), II (HDACs 4-7, 9 and 10) and IV (HDAC11) are all zinc-dependent metalloenzymes, while class III HDACs, also known as the sirtuins (SIRT1-7), requires NAD + as a cofactor for their catalytic function [6,14].Extensive efforts over recent decades have led to the identification of four chemically diverse classes of HDACIs as potent antineoplastic agents including, hydroxamates, benzamides, cyclic peptides, and short-chain fatty acids [3]. The main...

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Synthesis, Molecular Modelling and Biological Studies of 3-hydroxypyrane- 4-one and 3-hydroxy-pyridine-4-one Derivatives as HIV-1 Integrase Inhibitors

Cited by 21 publications

References 75 publications

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

Cinnamides Target Leishmania amazonensis Arginase Selectively

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

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