Potent HIV-1 Integrase Research Articles

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.

Discovery of potent HIV integrase inhibitors active against raltegravir resistant viruses

A series of novel HIV integrase inhibitors active against rategravir resistant strains are reported. Initial SAR studies revealed that activities against wild-type virus were successfully maintained at single digit nanomolar level with a wide range of substitutions. However, inclusion of nitrogen-based cyclic substitutions was crucial for achieving potency against mutant viruses. Several compounds with excellent activities against wild-type virus as well as against the viruses with the mutations Q148H/G140S or N155H/E92Q were reported.

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.

Electronic transitions of neutral and anionic quinolinone HIV-1 integrase inhibitor: Joint theory/experiment investigation

In this joint experimental and theoretical study, the solution-state conformation of [6-bromo-1-(4-fluorophenylmethyl)-4(1 H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid (QDKA), a potential HIV-1 integrase inhibitor, is investigated by using UV–visible spectroscopy and Time-Dependent Density Functional Theory. The neutral, mono-anionic and di-anionic species have been identified and their spectral characteristics rationalized. The possibility of forming enol tautomers and keto structures is assessed.

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.

N-(4-Fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamides a novel class of potent HIV-1 integrase inhibitors

A novel class of tetrahydro-pyrazinopyrimidine-2-carboxamides have been identified as HIV-1 integrase inhibitors. Optimization of the initial lead culminated in the discovery of a series of compounds with high potency on the enzyme and an antiviral cell-based activity equivalent to that showed by Raltegravir, the first in class HIV-1 integrase inhibitor.

Pharmacokinetic and Pharmacodynamic Predictions of Novel Potential HIV-1 Integrase Inhibitors

Virtual screening docking-based approach has been employed in order to select novel HIV-1 integrase (IN) potential inhibitors in large databases. Toxicity, metabolism and drug-like properties have been analyzed for the most promising compounds, using computational chemistry techniques. Results were compared and discussed with that obtained for a known HIV-1 (IN) inhibitor reported in the literature.

Routes to HIV-integrase inhibitors: efficient synthesis of bicyclic pyrimidones by ring expansion or amination at a benzylic position

Ring expansion of [6,6] bicyclic pyrimidones led, through an aziridinium intermediate, to potent HIV-integrase inhibitors with a [7,6] core. A more flexible and diversity-oriented synthesis of functionalized pyrimidohexahydrodiazepines was then developed; the key benzylic substituent was introduced in one pot by using sequentially DDQ and BnMeNH. Both synthetic routes are described.

Practical Synthesis of a HIV Integrase Inhibitor

A practical and efficient synthesis of the potent HIV integrase inhibitor 1 is described. Starting from readily available 3,4-dihydro-2H-pyran, the six-step synthesis features a through process without purification of any of the intermediates until the isolation of crystalline intermediate 7. After deprotection and classical resolution, amine 8 was isolated with excellent enantiopurity. A final amide coupling completed the synthesis of 1 in 7.6% overall yield from DHP. This chromatography-free route is more cost effective and increases the overall yield by nearly 3 times when compared with the original Med Chem synthethic route. This improved chemistry was used successfully to prepare multikilogram quantities of integrase inhibitor 1.

Design and Synthesis of Bis-amide and Hydrazide-containing Derivatives of Malonic Acid as Potential HIV-1 Integrase Inhibitors

HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. In the search for new IN inhibitors, we designed and synthesized three series of bis-amide and hydrazide-containing derivatives of malonic acid. We performed a docking study to investigate the potential interactions of the title compounds with essential amino acids on the IN active site.

Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 1. Synthesis and Structure−Activity Relationship of a Class of Human Immunodeficiency Virus type 1 Integrase Inhibitors

A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.

Investigation of formation of dimeric G-quadruplex of HIV-1 integrase inhibitor by nuclear magnetic resonance

In this research, an unusually dimeric G-quadruplex of d(GGGTGGGTGGGTGGGT) (S1), the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance (NMR). This result has been confirmed by electrospray ionization mass spectrometry (ESI-MS) and circular dichroism (CD).

Synthesis and anti-HIV-1 integrase activities of 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines

A series of novel 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines 15– 28 as potential HIV-1 integrase (IN) inhibitors have been synthesized by the reduction of 3-aroyl-1,1-dioxo-1,4,2-benzodithiazines 1– 14 with benzenesulfonyl hydrazide. All the compounds 15– 28 inhibited IN mediated strand transfer reaction with IC 50 values ranging from 3 to 30 μM. The 3-(4-bromobenzoyl)-6-chloro-7-methyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazine 17 with the IC 50 values of 4 ± 1 and 3 ± 1 μM for 3′-processing and strand transfer, respectively, was the most potent. Compound 17 as well its analogues were 5–20-fold less potent in Y99S and H114A mutants, implicating these residues as potential drug-binding site. This is a first report implicating Y99S and H114A of IN core domain in drug-binding interactions.

Investigation of Formation, Recognition, Stabilization, and Conversion of Dimeric G-Quadruplexes of HIV-1 Integrase Inhibitors by Electrospray Ionization Mass Spectrometry

The dimeric G-quadruplex structures of d(GGGTGGGTGGGTGGGT) (S1) and d(GTGGTGGGTGGGTGGGT) (S2), the potent nanomolar HIV-1 integrase inhibitors, were detected by electrospray ionization mass spectrometry (ESI-MS) for the first time. The formation and conversion of the dimers were induced by NH(4)(+), DNA concentration, pH, and the binding molecules. We directly observed the specific binding of a perylene derivative (Tel03) and ImImImbetaDp in one system consisting of the intramolecular and the dimeric G-quadruplexes of the HIV-1 integrase inhibitor, which suggested that Tel03 could shift the equilibrium to the dimeric G-quadruplex formation, while ImImImbetaDp induces preferentially a structural change from the dimer to the intramolecular G-quadruplex. The results of this study indicated that Tel03 and ImImImbetaDp favor the stabilization of the dimeric G-quadruplex structures.

Investigation of Novel Lipid-Functionalized PNA Monomers as Potential HIV-1 Non-Nucleoside Reverse Transcriptase and/or Integrase Inhibitors

A range of novel N-terminal lipid-functionalized peptide nucleic acid (PNA) monomers have been prepared and their abilities to inhibit HIV-1 reverse transcriptase and integrase have been examined.

Discovery of novel non-cytotoxic salicylhydrazide containing HIV-1 integrase inhibitors

The previously discovered salicylhydrazide class of compounds displayed potent HIV-1 integrase (IN) inhibitory activity. The development of this class of compounds as antiretroviral agents was halted due to cytotoxicity in the nanomolar to sub-micromolar range. We identified a novel class of non-cytotoxic hydrazide IN inhibitors utilizing the minimally required salicylhydrazide substructure as a template in a small-molecule database search. The novel hydrazides displayed low micromolar IN inhibitory activity and are several hundred-fold less cytotoxic than previously disclosed salicylhydrazide IN inhibitors.