Fernanda da C. Santos

Molecular design, synthesis and biological evaluation of 1,4-dihydro-4-oxoquinoline ribonucleosides as TcGAPDH inhibitors with trypanocidal activity.

The 1,4-dihydro-4-oxoquinoline ribonucleoside, Neq135, is the first low micromolar trypanosomatidae inhibitor to show good ligand efficiency (0.28 kcal mol(-1)atom(-1)) and good ligand lipophilicity efficiency (0.37 kcal mol(-1)atom(-1)) when acting against Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH). This and other six ribonucleosides were synthesized using our in-house technology, and assayed against the GAPDH NAD(+) site using isothermal titration calorimetry (ITC). Compound Neq135 had acceptable in vitro cytotoxicity, inhibited TcGAPDH with a Ki(app) value of 16 μM and killed the trypomastigote form of Trypanosoma cruzi Tulahuen strain with a concentration similar to that displayed by the control drug benznidazole. Neq135 is tenfold lower kinetic affinity against hGAPDH and does not kill Balb-c fibroblast nor spleen mouse cells. These results emphasize the possibility of integrating ligand- and target-based designs to uncover potent and selective TcGAPDH inhibitors that expands the opportunity for further medicinal chemistry endeavor towards NAD(+) TcGAPDH site.

Oxoquinoline derivatives: identification and structure-activity relationship (SAR) analysis of new anti-HSV-1 agents.

Herpes simplex virus is an important human pathogen responsible for a range of diseases from mild uncomplicated mucocutaneous infections to life-threatening ones. Currently, the emergence of Herpes simplex virus resistant strains increased the need for more effective and less cytotoxic drugs for Herpes treatment. In this work, we synthesized a series of oxoquinoline derivatives and experimentally evaluated the antiviral activity against acyclovir resistant HSV-1 strain as well as their cytotoxity profile. The most active compound (3b), named here as Fluoroxaq-3b, showed a promising profile with a better cytotoxicity profile than acyclovir. The theoretical analysis of the structure–activity relationship of these compounds revealed some stereoelectronic properties such as lower LUMO energy and lipophilicity, besides a higher polar surface area and number of hydrogen bond acceptor groups as important parameters for the antiviral activity. Fluoroxaq-3b showed a good oral theoretical bioavailability, according to Lipinski rule of five, with a promising profile for further in vivo analysis.

Synthesis and Anti-HSV-1 In Vitro Activity of New Phosphoramidates with 4-oxoquinoline and Phtalimidic Nuclei

Abstract: Aminoalkyl phosphoramidates were obtained by either direct phosphorylation of symmetric diamines or a three steps method analogue to Gabriel’s synthesis and coupled to a 4-oxoquinoline acyclonucleoside, in order to synthesize 4-oxoquinolone phosphoramidates. Two unpublished compounds demonstrated low cytotoxity in comparison to Acyclovir and good HSV-1 cytophatic effects on Acyclovir resistant strains. Keywords: Aminoalkyl phosphoramidates, 4-oxoquinoline acyclonucleoside, nucleotide analogues, Herpes Simplex Virus type 1 (HSV-1). 1. INTRODUCTION Herpes Simplex Virus type 1 (HSV-1) is a large, envel-oped DNA containing virus with a genome of approximately 152 kb. In humans infection usually begins on the skin or mucosal epithelium and subsequently spreads to the sensory ganglia whose nerve processes contact the primary site of infection. Once inside these neurons the virus can enter a dormant state characterized by the absence of lytic gene tran-scription [1]. Periodic reactivation of the dormant virus can lead to the development of infective and painful facial le-sions. Acyclovir (ACV) is used clinically as an anti-herpes drug. However, with increasing use of antiviral drugs there is an increased risk that resistant strains may develop. The her-pes viruses, for example, have been shown to acquire resis-tance to ACV in immunocompromised patients [2]. The de-velopment of new antivirals that have a wide range of effi-cacy against pre-existing and resistant strains, but that lack serious adverse effects, would clearly be advantageous. However, only a few compounds have reached prominence at the clinical level so far. A large number of compounds within the group of acyclic nucleosides demonstrate antiviral activity [3-7] and as such have prompted recent research in-terest due to their clinical potential. Most current anti-herpes drugs are inactive until phosphorylated by viral timidine kinase (TK) inside the target cell so that viruses lacking TK are at an advantage. Phosphorylated nucleoside analogues lack the ability to cross the plasma membrane due to the high anionic charge of the phosphate groups. This unsuitability for therapeutic use is compounded by the action of non-specific stearases in the cytoplasm which cleave and render them inactive [8-9]. To overcome these obstacles phosphonates have been developed