6-chloro-1-4-dihydro-4-oxo-1-(beta-d-ribofuranosyl)quinoline-3-carboxylic-acid and HIV-Infections

In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives. The structure-activity relationship analysis revealed some stereoelectronic properties such as LUMO energy, dipole moment, number of rotatable bonds, and of hydrogen bond donors and acceptors correlated with the potency of compounds. We also describe the importance of substituents R(2) and R(3) for their biological activity. Compound 2j was identified as a lead compound for future investigation due to its: (i) high activity against HIV-1, (ii) low cytotoxicity in PBMC, (iii) low toxic risks based on in silico evaluation, (iv) a good theoretical oral bioavailability according to Lipinski 'rule of five', (v) higher druglikeness and drug-score values than current antivirals AZT and efavirenz.

Topics: Animals; Anti-HIV Agents; Cell Survival; Chlorocebus aethiops; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Models, Molecular; Molecular Structure; Quinolones; Structure-Activity Relationship; Vero Cells

We describe in this paper that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl)-quinoline-3-carboxylic acid (compound A) inhibits the HIV-1 replication in human primary cells. We initially observed that compound A inhibited HIV-1 infection in peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner, resulting in an EC(50) of 1.5 +/- 0.5 microM and in a selective index of 1134. Likewise, compound A blocked HIV-1(BA-L) replication in macrophages in a dose-dependent manner, with an EC(50) equal to 4.98 +/- 0.9 microM. The replication of HIV-1 isolates from subtypes C and F was also inhibited by compound A with the same efficiency. Compound A inhibited an early event of the HIV-1 replicative cycle, since it prevented viral DNA synthesis in PBMCs exposed to HIV-1. Kinetic assays demonstrated that compound A inhibits the HIV-1 enzyme reverse transcriptase (RT) in dose-dependent manner, with a K(I) equal to 0.5 +/- 0.04 microM. Using a panel of HIV-1 isolates harboring NNRTI resistance mutations, we found a low degree of cross-resistance between compound A and clinical available NNRTIs. In addition, compound A exhibited additive effects with the RT inhibitors AZT and nevirapine, and synergized with the protease inhibitor atazanavir. Our results encourage continuous studies about the kinetic impact of compound A towards different catalytic forms of RT enzyme, and suggest that our nucleoside represents a promising molecule for future antiretroviral drug design.

Topics: Anti-HIV Agents; Cell Survival; DNA Replication; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Macrophages; Quinolines; Reverse Transcriptase Inhibitors; Ribonucleosides; Virus Replication