The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism.

In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death.

Further optimization of plakortin pharmacophore: structurally simple 4-oxymethyl-1,2-dioxanes with promising antimalarial activity.

For the optimization of the plakortin pharmacophore, we recently proposed a straightforward synthesis of 4-carbomethoxy-3-methoxy-1,2-dioxanes as potential antimalarial drug candidates. Herein we report the chemoselective reduction of the 4-carbomethoxy group which has allowed us to prepare in good yields twenty-four new endoperoxides carrying either the hydroxymethyl or the methoxymethyl group on C4 in various stereochemical arrangements with respect to the alkyl groups on C3 and C6 (the endoperoxide carbons). Some of these compounds showed promising in vitro antimalarial activities, both against chloroquine-resistant (CQ-R) and susceptible (CQ-S) strains of Plasmodium falciparum, with IC₅₀ values in the range of 0.

A new class of antimalarial dioxanes obtained through a simple two-step synthetic approach: rational design and structure-activity relationship studies.

A new series of simple endoperoxides, characterized by a 3-methoxy-1,2-dioxane scaffold, was designed on the basis of a previously developed pharmacophore. Through a simplified and versatile scheme of synthesis, which utilizes cheap and commercially available starting materials, it was possible to obtain several structurally and stereochemically different compounds that were tested against P. falciparum.

Oxime amides as a novel zinc binding group in histone deacetylase inhibitors: synthesis, biological activity, and computational evaluation.

Several oxime containing molecules, characterized by a SAHA-like structure, were explored to select a potentially new biasing binding element for the zinc in HDAC catalytic site. All compounds were evaluated for their in vitro inhibitory activity against the 11 human HDACs isoforms. After identification of a "hit" molecule, a programmed variation at the cap group and at the linker was carried out in order to increase HDAC inhibition and/or paralogue selectivity.

Pyranoanthocyanins: a theoretical investigation on their antioxidant activity.

The antioxidant radical scavenging capacity of pyranoanthocyanins present in aged wine and coming from the chemical transformation undergone by anthocyanins was theoretically explored by DFT/B3LYP methods. The two main working mechanisms (H atom donation and single-electron transfer) were investigated, and the O-H bond dissociation energy (BDE) and ionization potential (IP) parameters were computed in the gas phase and in water and benzene solutions. Results indicated that systems possessing the catechol functionality as well as the o-dimethoxy motif are good candidates to donate a H atom to the free radicals, inactivating them.

On the origin of the different performance of iron and manganese monocations in catalyzing the nitrous oxide reduction by carbon oxide.

The potential energy profiles for the Fe+- and Mn+-assisted reduction of N2O by CO were studied at the B3LYP density functional level in order to get the differences in the reaction mechanisms determining the efficiency of iron and the inactivity of manganese as ionic catalysts. Both ground and excited states of cations were taken into account in view of a possible participation of the highest multiplicities to the reduction process. Results indicated that a spin inversion occurs in the rate-determining step of iron ion-catalyzed reaction that improves the performance of the cation.