New 2-alkylthio-1-benzylimidazole-5-carboxylic acid derivatives targeting gp41: design, synthesis and in vitro anti-HIV activity evaluation.

Background Although current available medications have increased the quality of life in HIV-infected patients, there are still some shortcomings in HIV treatment arising from viral resistance, drug side effects and high cost of medication. Therefore, there is an urgent need for some suitable HIV inhibitors with different mechanisms of action. Gp41, located on the HIV cell surface, plays an important role in the fusion of viral and host cell membranes. With the same structure in different HIV strains, gp41 seems to be a promising target for developing novel HIV fusion inhibitors. Objective Based on the essential structural elements of gp41 inhibitors, two series of compounds were prepared and their inhibitory effect on HIV cell growth was investigated. Compared to the known small-molecule gp41 inhibitors, 2-Alkylthio-1-benzylimidazole-5-carboxylic acid (series I) and (E)-4-{[5-(((1-benzyl-1H-1,2,3-triazol-4-yl)methoxyimino)methyl)-2-(alkylthio)-1H-imidazol-1-yl]methyl}benzoic acid derivatives (series II) had more flexible skeleton with extra moieties interacting with the gp41 key residues. Method In silico drug design approaches including molecular docking and molecular dynamics simulations were employed to design these novel compounds prior to preparation. The designed compounds exhibited proper chemical interactions and stable complexes with gp41. Then, the selected candidates were efficiently synthesized, and their anti-HIV-1 and anti-HIV-2 activities, as well as their cellular cytotoxicity in MT-4 cells were determined. Results None of the compounds belonging to the series I were active against HIV-1 and HIV-2 replication in cell cultures, and most of the compounds in series II exhibited significant cytotoxicity against MT-4 cells in low micro molar concentrations. Conclusion The smaller molecular structures of the compounds in series I might be responsible for their poor anti-HIV effects. The high toxicity of the series II compounds on the host cell makes it impossible to assess their anti-HIV activities.

Design, synthesis, in silico studies, and antiproliferative evaluations of novel indolin-2-one derivatives containing 3-hydroxy-4-pyridinone fragment.

Keeping in view the pharmacological properties of indolinones as promising scaffold as kinase inhibitors, herein, a novel series of 3-hydrazonoindolin-2-one derivatives bearing 3-hydroxy-4-pyridinone moiety were synthesized, studied by molecular docking, and fully characterized by spectroscopic techniques. All the prepared compounds were evaluated for their cytotoxicity attributes against a panel of tumor cell lines, including non-small cell lung cancer (A549), breast carcinoma (MCF-7), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). They displayed moderate to promising antiproliferative effects toward A549 and MCF-7 cells but remarkable results against AML and CML. Especially, compound 10k was found to be more potent against AML (EC50 = 0.69 µM) compare to the other halogen-substituted derivatives. FMS-like tyrosine kinase 3 (FLT3) is known to be expressed in AML cancer cells. The molecular docking studies demonstrated that our prepared compounds were potentially bound to AML active site through essential H-bond and other vital interactions with critical binding residues.

In silico design of novel FAK inhibitors using integrated molecular docking, 3D-QSAR and molecular dynamics simulation studies.

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a crucial role in integrin signaling that regulates essential cellular functions including growth, motility, proliferation and survival in different types of cells. Interestingly, it has also shown to be up-regulated in various types of tumors, hence it has emerged as a significant therapeutic target for the development of selective inhibitors. In present work, with the aim of achieving further insight into the structural characteristics required for the FAK inhibitory activity, a combined approach of molecular modeling studies including molecular docking, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular dynamics (MD) simulation were carried out on a series of 7H-pyrrolo[2,3-d]pyrimidine and thieno[3,2-d]pyrimidine FAK inhibitors. The probable binding modes and interactions of inhibitors into the FAK active site were predicted by molecular docking. The 3D-QSAR models were developed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods, with three ligand-based, docking-based and receptor-based alignment techniques. Both CoMFA and CoMSIA models obtained from receptor-based alignment were superior to the ones obtained by other alignment methods. However, the CoMSIA model (q2 = 0.679, r2 = 0.954 and r2pred = 0.888) depicted almost better predictive ability than the CoMFA model (q2 = 0.617, r2 = 0.932 and r2pred = 0.856). The contour map analysis revealed the relationship between the structural features and inhibitory activity. The docking results and CoMFA and CoMSIA contour maps were in good accordance. Based on the information obtained from the molecular docking and contour map analysis, a series of novel FAK inhibitors were designed that showed better predicted inhibitory activity than the most potent compound 31 in the data set. Finally, the stability of the reference molecule 31 and the designed compounds D15 and D27 were evaluated through a 30 ns of MD simulation and their binding free energies were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The result of MD simulation and binding free energy decomposition demonstrated the important role of van der Waals interactions alongside H-bond ones that were in consistent with the docking and contour maps analysis results. In sum, the results from this study may provide a significant insight for developing more effective novel FAK inhibitors.Communicated by Ramaswamy H. Sarma.

Recent Advances in the Design and Development of Non-nucleoside Reverse Transcriptase Inhibitor Scaffolds.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have always been an important part of the anti-HIV-1 combination therapy known as combination antiretroviral therapy (cART) since 1996. The use of NNRTIs for about 22 years has led to some mutations in the residues that compose the reverse transcriptase active site, resulting in the emergence of drug-resistant viruses. Thus, the search for new potent NNRTIs with an improved safety profile and activity against drug-resistant HIV strains is indispensable, and many hit and lead NNRTIs have been discovered in the last decade. This review provides an overview of the development in this field from 2013 to August 2018.

2-(3,5-Dioxo-4-aza-tri-cyclo-[5.2.1.0(2,6)]dec-8-en-4-yl)acetic acid.

The asymmetric unit of the title compound, C11H11NO4, contains two mol-ecules, A and B, with different conformations: in mol-ecule A, the norborne and carb-oxy-lic acid groups lie to the same side of the heterocycle, whereas in a mol-ecule B, they lie on opposite sides. In the crystal, the A mol-ecules form R 2 (2)(8) carb-oxy-lic acid inversion dimers, linked by pairs of O-H⋯O hydrogen bonds. The B mol-ecules link to one of the ketone O atoms of the A mol-ecule by an O-H⋯O inter-action, resulting in tetra-mers (two A and two B mol-ecules). The tetra-mers are linked by weak C-H⋯O inter-actions, generating a three-dimensional network.