Potential HIV-1 Integrase Inhibitors Research Articles

Design, Practical Synthesis, and Biological Evaluation of Novel 6-(Pyrazolylmethyl)-4-quinoline-3-carboxylic Acid Derivatives as HIV-1 Integrase Inhibitors

A series of novel 6-(pyrazolylmethyl)-4-oxo-4H-quinoline-3-carboxylic acid derivatives bearing different substituents on the N-position of quinoline ring were designed and synthesized as potential HIV-1 integrase (IN) inhibitors, based on the structurally related GS-9137 scaffold. The structures of all new compounds were confirmed by 1H-NMR, 13C-NMR and ESI (or HRMS) spectra. Detailed synthetic protocols and the anti-IN activity studies are also presented.

POM as a quick bioinformatic platform to select flavonoids and their metabolites as potential and efficient HIV-1 integrase inhibitors

This paper surveys the various naturally occurring flavonoids that have been isolated from different natural sources. This is the first petra/osiris/molinspiration (POM) analysis published on this topic. The present study furnishes an overview of the 32 flavonoids and anti-HIV-Integrase activity of their metabolite species. The aqueous and/or ethanol extraction of flavonoids have often been used in traditional medicine, and therefore have also been studied for their antitumor, antioxidant, antiviral, anti-algal, antimicrobial, cytotoxic and anti-inflammatory, and significant hepatoprotective and cardiovascular activity without any criteria of selection. Here, on the basis of POM analyses, a simple, economic, quick and efficient bioinformatic platform, it now becomes easy and possible to predict and optimize flavonoids bioactivity.

Absolute configurations of integracins A, B, and 15′‐dehydroxy‐integracin B

Integracins A (1) and B (2), potent HIV-1 integrase inhibitors, and 15'-dehydroxy-integracin B (3) were isolated for the first time from Chinese mangrove plant Sonneratia hainanensis. Their absolute configurations were determined by the Mosher's method and specific rotation analysis of alcohols (6 and 7) obtained from integracin A in two steps and by chemical correlation. Integracin A (1) also exhibited significant cytotoxicity against the tumor cell lines HepG2 and NCI-H460 with both 100% inhibitions at 25 µg/ml.

Synthesis and biological evaluation of 5-fluoroquinolone-3-carboxylic acids as potential HIV-1 integrase inhibitors

A series of new quinolone-3-carboxylic acids as HIV-1 integrase inhibitors featuring a fluorine atom at C-5 position were synthesized and evaluated for their antiviral activity in C8166 cell culture. These newly synthesized compounds showed anti-HIV activity against wild-type virus with an EC50 value ranging from 29.85 to 0.032 μΜ. The most active compound 4e exhibited activity against wild-type virus and the mutant virus A17 with an EC50 value of 0.032 and 0.082 μΜ, respectively. Preliminary structure–activity relationship of these 5-fluoroquinolone-3-carboxylic acids was also investigated.

Homology model-guided 3D-QSAR studies of HIV-1 integrase inhibitors.

In the present study, we report the exploration of binding modes of potent HIV-1 integrase (IN) inhibitors MK-0518 (raltegravir) and GS-9137 (elvitegravir) as well as chalcone and related amide IN inhibitors we recently synthesized and the development of 3D-QSAR models for integrase inhibition. Homology models of DNA-bound HIV-1 IN were constructed on the basis of the X-ray crystal structure of the foamy virus IN-DNA complex (PDB ID: 3L2T ) and used for docking. The binding modes of raltegravir and elvitegravir in our homology models are in accordance with those in the foamy virus structure revealing interactions important for inhibitor-IN binding. To gain further insights into the structural requirements for IN inhibition, three-dimensional quantitative structure activity relationship (3D-QSAR) studies were conducted using raltegravir, elvitegravir, and their analogs; our synthesized 3-keto salicylic acid IN inhibitor series; as well as other structurally related HIV-1 IN inhibitors. In the first part of the study with 103 compounds, atom-fit alignments, I and II, and docking-based alignment, III, were used to develop 3D-QSAR models 1, 2, and 3, respectively, each comprising comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSARs. This initial analysis indicated that the docking-based (structure-based) model 3 performed better than the atom-fit (ligand-based) models 1 and 2, in terms of statistical significance and robustness. Thus, the docking-based alignment was then subsequently used with an expanded data set of 296 compounds for building a more comprehensive 3D-QSAR, model 4. Model 4 afforded good q² values of 0.70 and 0.75 for CoMFA and CoMSIA 3D-QSARs, respectively, and showed good predictive performance on an external validation test set of 59 compounds with predictive r² values up to 0.71. The HIV IN-DNA homology model of biological relevance and the comprehensive 3D-QSAR models developed in the present study provide insights and new predictive tools for structure-based design and optimization of IN inhibitors.

Design and synthesis of novel β-diketo derivatives as HIV-1 integrase inhibitors

A series of novel β-diketo derivatives which combined the virtues of 1,3-diketo, 1,2,3-triazole and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and evaluated their inhibition to the strand transfer process of HIV-1 integrase. The result indicates that 3,4,5-trihydroxylated aromatic derivatives exhibit good inhibition to HIV-1 integrase, but dihydroxylated aromatic derivatives and corresponding methoxy aromatic derivatives appear little inhibition to HIV-1 integrase.

Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase

HIV-1 integrase is an essential enzyme for viral replication and a validated target for the development of drugs against AIDS. With an aim to discover new potent inhibitors of HIV-1 integrase, we developed a pharmacophore model based on reported inhibitors embodying structural diversity. Eight compounds of 2-pyrrolinones fitting all the features of the pharmacophore query were found through the screening of an in-house database. These candidates were successfully synthesized, and three of them showed strand transfer inhibitory activity, in which, one compound showed antiviral activity. Further mapping analysis and docking studies affirmed these results.

Microwave Assisted Organic Synthesis (MAOS) of Small Molecules as Potential HIV-1 Integrase Inhibitors

Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). In recent years our research group has been engaged in the stucture-function study of this enzyme and in the development of some three-dimensional pharmacophore models which have led to the identification of a large series of potent HIV-1 integrase strand-transfer inhibitors (INSTIs) bearing an indole core. To gain a better understanding of the structure-activity relationships (SARs), herein we report the design and microwave-assisted synthesis of a novel series of 1-H-benzylindole derivatives.

Synthesis and biological evaluation of HQCAs with aryl or benzyl substituents on N-1 position as potential HIV-1 integrase inhibitors

A series of new 5-hydroxylquinolone-3-carboxylic acids (HQCAs) with various aryl or benzyl substituents on N-1 position were synthesized and evaluated for their anti-HIV activity in C8166 cell culture. Most of the target compounds displayed activity against wide-type HIV-1 in the low micromolar range in infected C8166 cells. The most active compound 5g exhibited activity against wild-type HIV-1 and HIV-1 mutant virus A17 with an EC50 value of 3.17 and 17.88μM, respectively. The biological results and the docking study revealed that the substitution pattern on N-1 position of the quinolone core might contribute to physicochemical properties of HQCAs and resulted in great influence on their antiviral potency.

4-[1-(4-Fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid as a prototype to develop dual inhibitors of HIV-1 integration process

In recent years several potent HIV-1 integrase (IN) inhibitors have been identified and after the successful clinical use of raltegravir, they have gained a definitive place in the treatment of HIV-1 infection. Yet, there is a continuous effort to design newer inhibitors that target different steps in the integration process. Furthermore, the increased understanding of IN structural biology has opened novel approaches to inhibit IN, such as targeting its multimerization or interaction with cellular cofactors. On these bases, we have concentrated our research on the identification of small molecules able to inhibit two different stages of the integration process: the IN strand-transfer phase and the IN–LEDGF/p75 interaction. We found that the 4-[1-(4-fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (CHI-1043) is an interesting anti-HIV agent exhibiting dual inhibitory effects. This work has suggested the possibility of also constructing an integration dual inhibitor using a design-in strategy.

Baylis–Hillman-derived N,N′-disubstituted piperazines: structural and preliminary computational studies

Exploratory studies towards the preparation of potential HIV-1 protease and integrase inhibitors have led to the synthesis of Baylis–Hillman-derived N,N′-disubstituted piperazines. X-ray crystallographic, computer modelling and NMR techniques have been used to elucidate questions concerning configurational preferences, reaction pathways and the apparent difference in susceptibility towards aza-Michael reactions exhibited by methyl acrylate and methyl vinyl ketone (MVK) derived Baylis–Hillman substrates.

Virtual screening for natural product inhibitors of HIV-1 integrase

Since there is no human homolog of this enzyme, HIV-1 integrase (IN) represents a rational and important target for treating HIV infection and preventing AIDS. The 3D structure of full-length HIV-1 IN, either separately or in complex with its inhibitors, has been lacking. Thus, scarce information about the interactions between the HIV-1 IN and its inhibitors can be referenced. To more rationally design potent HIV-1 IN inhibitors, we have previously constructed a model of the full-length HIV-1 IN tetramer and a model of the protein-viral DNA complex, as well as the pharmacophore model of HIV-1 IN strand transfer inhibitors (INSTIs). In this paper, the pharmacophore model of INSTIs was used as a 3D query to screen the Traditional Chinese Medicine Database (TCMD). The hit compounds were further filtered by Lipinski's Rule of Five and docking study to refine the retrieved hits. Finally, 9 suitable ligands with similar structures belonging to the thioglycosides were selected. Subsequent molecular dynamics simulation showed that these compounds had interactions with HIV-1 IN binding site and their possible function as IN inhibitors was discussed.

Synthesis, biological evaluation and molecular modeling studies of quinolonyl diketo acid derivatives: New structural insight into the HIV-1 integrase inhibition

New quinolonyl diketo acid compounds bearing various substituents at position 6 of the quinolone scaffold were designed and synthesized as potential HIV-1 integrase inhibitors. These new compounds were evaluated for their antiviral and anti-integrase activity and showed inhibitory potency similar to that of 6-bromide analog 2. Molecular modeling and docking studies were performed to rationalize these data and to provide a detailed understanding of the mechanism of inhibition for this class of compounds.

The evaluation of catechins that contain a galloyl moiety as potential HIV-1 integrase inhibitors

Four catechins with the galloyl moiety, including catechin gallate (CG), epigallocatechin gallate (EGCG), gallocatechin gallate (GCG), and epicatechin gallate (ECG), were found to inhibit HIV-1 integrase effectively as determined by our ELISA method. In our docking study, it is proposed that when the HIV-1 integrase does not combine with virus DNA, the four catechins may bind to Tyr143 and Gln148, thus altering the flexibility of the loop (Gly140-Gly149), which could lead to an inhibition of HIV-1 integrase activity. In addition, after combining HIV-1 integrase with virus DNA, the four catechins may bind between the integrase and virus DNA, consequently, disrupt this interaction. Thus, the four catechins may reduce the activity of HIV-1 integrase by disrupting its interaction with virus DNA. The four catechins have a highly cooperative inhibitory effect (IC 50 = 0.1 μmol/L). Our study suggests that catechins with the galloyl moiety could be a novel and effective class of HIV-1 integrase inhibitors.

Synthesis of polyhydroxylated aromatics having amidation of piperazine nitrogen as HIV-1 integrase inhibitor

( E)- N-[3-(4-Cinnamoylpiperazin-1-yl)propyl]-3,4-dihydroxybenzamide and ( E)- N-[3-(4-cinnamoylpiperazin-1-yl)propyl]-3,4,5-trihydroxybenzamide were designed and synthesized as potential HIV-1 integrase inhibitors and evaluated their inhibition to the strand transfer process of HIV-1 integrase. The result indicates that 3,4,5-trihydroxylated aromatic derivatives exhibit good inhibition to HIV-1 integrase, however, corresponding 3,4-dihydroxylated aromatic derivatives appear little inhibition of HIV-1 integrase.

CoMFA and CoMSIA 3D-QSAR studies on quionolone caroxylic acid derivatives inhibitors of HIV-1 integrase

A series of quionolone caroxylic acid derivatives inhibitors of HIV-1 integrase were subjected to three-dimensional quantitative structure–activity relationship (3D-QSAR) studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The CoMFA model includes steric and electrostatic fields for the training set with the cross-validated q 2 value of 0.67 and the non-cross-validated r 2 value of 0.98. The cross-validated q 2 value of CoMSIA Model is 0.76 and the non-cross-vaildated r 2 value is 0.99. From the cross-validated results, it can be seen that the CoMSIA model has a better predictive ability than CoMFA model. Based on the above results, the CoMFA and CoMSIA analyses can be used in the design of more potent HIV-1 integrase inhibitors.

Solid Phase Synthesis of Novel Pyrrolidinedione Analogs as Potent HIV-1 Integrase Inhibitors

A novel series of HIV-1 integrase inhibitors were identified from a 100 member (4R(1) x 5R(2) x 5R(3)) library of pyrrolidinedione amides. A solid-phase route was developed which facilitates the simultaneous variation at R(1), R(2), and R(3) of the pyrrolidinedione scaffold. The resulting library samples were assayed for HIV-1 integrase activity and analyzed to determine the R(1), R(2), and R(3) reagent contributions towards the activity.

Azaindole Hydroxamic Acids are Potent HIV-1 Integrase Inhibitors

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors.

The 3D structures of G-Quadruplexes of HIV-1 integrase inhibitors: molecular dynamics simulations in aqueous solution and in the gas phase

The unimolecular G-quadruplex structures of d(GGGTGGGTGGGTGGGT) (G1) and d(GTGGTGGGTGGGTGGGT) (G2) are known as the potent nanomolar HIV-1 integrase inhibitors, thus investigating the 3D structures of the two sequences is significant for structure-based rational anti-HIV drug design. In this research, based on the experimental data of circular dichroism (CD) spectropolarimetry and electrospray ionization mass spectrometry (ESI-MS), the initial models of G1 and G2 were constructed by molecular modeling method. The modeling structures of G1 and G2 are intramolecular parallel-stranded quadruplex conformation with three guanine tetrads. Particularly, the structure of G2 possesses a T loop residue between the first and the second G residues that are the component of two adjacent same-stranded G-tetrad planes. This structure proposed by us has a very novel geometry and is different from all reported G-quadruplexes. The extended (35 ns) molecular dynamic (MD) simulations for the models indicate that the G-quadruplexes maintain their structures very well in aqueous solution whether the existence of K(+) or NH (4) (+) in the central channel. Furthermore, we perform 500 ns MD simulations for the models in the gas phase. The results show that all the ion-G-quadruplex complexes are maintained during the whole simulations, despite the large magnitude of phosphate-phosphate repulsions. The gas phase MD simulations provide a good explanation to ESI-MS experiments. Our 3D structures for G1 and G2 will assist in understanding geometric formalism of G-quadruplex folding and may be helpful as a platform for rational anti-HIV drug design.

Structural and theoretical studies of [6-bromo-1-(4-fluorophenylmethyl)-4(1 H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid as HIV-1 integrase inhibitor

Ethyl [6-bromo-1-(4-fluorophenylmethyl)-4(1 H)-quinolinon-3-yl]-4-hydroxy-2-oxo-3-butenoate 1 and [6-bromo-1-(4-fluorophenylmethyl)-4(1 H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid 2 were synthesized as potential HIV-1 integrase inhibitors and evaluated for their enzymatic and antiviral activity, acidic compound 2 being more potent than ester compound 1. X-ray diffraction analyses and theoretical calculations show that the diketoacid chain of compound 2 is preferentially coplanar with the quinolinone ring (dihedral angle of 0–30°). Docking studies suggest binding modes in agreement with structure–activity relationships.