Giuseppe Paglietti

Bio: Giuseppe Paglietti is an academic researcher from University of Sassari. The author has contributed to research in topics: Quinoxaline & Dihydrofolate reductase. The author has an hindex of 24, co-authored 125 publications receiving 2016 citations.

Chemistry, biological properties and SAR analysis of quinoxalinones.

Abstract: Quinoxaline derivatives have received much attention in recent years owing to their both biological properties and pharmaceutical applications. In this review we focus the attention on quinoxalin-2(3)-ones and quinoxalin-2,3-diones. These derivatives are particularly interesting since some of them showed antimicrobial (against several bacteria, viruses, fungi, etc), or anticancer activities. Furthermore, others are reported to be potent no-NMDA glutamate receptor antagonists, endowed with anxiolytic, deconditioning, analgesic, antispastic, antiallergic, antithrombotic activities. In this article we also report SAR studies and the most important methods of synthesis of the quinoxalin-2(3)-(di)ones.

Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development

Abstract: Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes Compound 6a displayed a Ki of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved Ki (37 nM) against LmPTR1, and the structure of this complex was also determined Biological evaluation of selected inhibitors was performed against the extracellular forms of T cruzi and L major, both wild-type and overexpressing PTR1 lines, as a model for PTR1-driven antifolate drug resistance and the intracellular form of T cruzi An additive profile was observed when PTR1 inhibitors were used in combination with known DHFR inhibitors, and a reduction in toxicity of treatment was observed with respect to administration of a DHFR inhibitor alone The successful combination of antifolates targeting two enzymes indicates high potential for such an approach in the development of previously undescribed antiparasitic drugs

Quinoxaline chemistry. Part 7. 2-[aminobenzoates]- and 2-[aminobenzoylglutamate]-quinoxalines as classical antifolate agents. Synthesis and evaluation of in vitro anticancer, anti-HIV and antifungal activity.

Abstract: Thirty-three quinoxalines bearing an aminobenzoyl or aminobenzoylglutamate group on position 2 and various substituents on position 3,6,7 of the heterocycle were prepared in order to evaluate in vitro anticancer activity. Preliminary screening performed at NCI showed that most derivatives exhibited a moderate to strong growth inhibition activity on various tumor panel cell lines between 10(-5) and 10(-4) Molar concentrations. Interesting selectivities were also recorded between 10(-8) and 10(-6) M. Among the series examined one compound (29) which was the most active also exhibited both in vitro anti-HIV protection and antifungal activity while in other two (31, 37) the antifungal activity was prevailing.

Protein drug stability: a formulation challenge

Abstract: The increasing use of recombinantly expressed therapeutic proteins in the pharmaceutical industry has highlighted issues such as their stability during long-term storage and means of efficacious delivery that avoid adverse immunogenic side effects. Controlled chemical modifications, such as substitutions, acylation and PEGylation, have fulfilled some but not all of their promises, while hydrogels and lipid-based formulations could well be developed into generic delivery systems. Strategies to curb the aggregation and misfolding of proteins during storage are likely to benefit from the recent surge of interest in protein fibrillation. This might in turn lead to generally accepted guidelines and tests to avoid unforeseen adverse effects in drug delivery.

A comprehensive review on tyrosinase inhibitors.

Abstract: Tyrosinase is a multi-copper enzyme which is widely distributed in different organisms and plays an important role in the melanogenesis and enzymatic browning. Therefore, its inhibitors can be attractive in cosmetics and medicinal industries as depigmentation agents and also in food and agriculture industries as antibrowning compounds. For this purpose, many natural, semi-synthetic and synthetic inhibitors have been developed by different screening methods to date. This review has focused on the tyrosinase inhibitors discovered from all sources and biochemically characterised in the last four decades.