Computational analysis and physico-chemical characterization of an inclusion compound between praziquantel and methyl-beta-cyclodextrin for use as an alternative in the treatment of schistosomiasis

Schistosomiasis is still an endemic disease in many regions, with 250 million people infected with Schistosoma and about 500,000 deaths per year. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment, however it is classified as Class II in the Biopharmaceutics Classification System, as its low solubility hinders its performance in biological systems. The use of cyclodextrins is a useful tool to increase the solubility and bioavailability of drugs. The aim of this work was to prepare an inclusion compound of PZQ and methyl-beta-cyclodextrin (MeCD), perform its physico-chemical characterization, and explore its in vitro cytotoxicity. SEM showed a change of the morphological characteristics of PZQ:MeCD crystals, and IR data supported this finding, with changes after interaction with MeCD including effects on the C-H of the aromatic ring, observed at 758 cm(-1). Differential scanning calorimetry measurements revealed that complexation occurred in a 1:1 molar ratio, as evidenced by the lack of a PZQ transition temperature after inclusion into the MeCD cavity. In solution, the PZQ UV spectrum profile in the presence of MeCD was comparable to the PZQ spectrum in a hydrophobic solvent. Phase solubility diagrams showed that there was a 5.5-fold increase in PZQ solubility, and were indicative of a type A(L) isotherm, that was used to determine an association constant (K(a)) of 140.8 M(-1). No cytotoxicity of the PZQ:MeCD inclusion compound was observed in tests using 3T3 cells. The results suggest that the association of PZQ with MeCD could be a good alternative for the treatment of schistosomiasis.

Adenine as an organocatalyst for the ring-opening polymerization of lactide: scope, mechanism and access to adenine-functionalized polylactide

Nucleobase-functionalized polymers are widely used in the fields of supramolecular chemistry and self-assembly, and their development for biomedical applications is also an area of interest. They are usually synthesized by tedious multistep procedures. In this study, we assess adenine as an organoinitiator/ organocatalyst for the ring-opening polymerization of lactide. L-Lactide can be quantitatively polymerized in the presence of adenine. Reaction conditions involving short reaction times and relatively low temperatures enable the access to adenine end-capped polylactide in a simple one-step procedure, in bulk, without additional catalyst. DFT calculations show that the polymerization occurs via hydrogen bond catalysis. The mechanism involves (i) a hydrogen bond between the NH9 of adenine and the carbonyl moiety of lactide, leading to an electron deficient carbon atom, and (ii) a second hydrogen bond between the N3 of adenine and the NH2 of a second adenine molecule, followed by a nucleophilic attack of the latter activated amine on the former electron deficient carbon on the monomer. For longer reaction times and higher temperatures, macrocyclic species are formed, and a mechanism involving the imidazole ring of adenine is proposed based on literature studies. Depending on the reaction conditions, adenine can thus be considered as an organoinitiator or an organocatalyst for the ring-opening polymerization of lactide.

Adenine as an organocatalyst for the ring-opening polymerization of lactide: scope, mechanism and access to adenine-functionalized polylactide

Nucleobase-functionalized polymers are widely used in the fields of supramolecular chemistry and self-assembly, and their development for biomedical applications is also an area of interest. They are usually synthesized by tedious multistep procedures. In this study, we assess adenine as an organoinitiator/organocatalyst for the ring-opening polymerization of lactide. L-Lactide can be quantitatively polymerized in the presence of adenine. Reaction conditions involving short reaction times and relatively low temperatures enable the access to adenine end-capped polylactide in a simple one-step procedure, in bulk, without additional catalyst. DFT calculations show that the polymerization occurs via hydrogen bond catalysis. The mechanism involves (i) a hydrogen bond between the NH9 of adenine and the carbonyl moiety of lactide, leading to an electron deficient carbon atom, and (ii) a second hydrogen bond between the N3 of adenine and the NH2 of a second adenine molecule, followed by a nucleophilic attack of the latter activated amine on the former electron deficient carbon on the monomer. For longer reaction times and higher temperatures, macrocyclic species are formed, and a mechanism involving the imidazole ring of adenine is proposed based on literature studies. Depending on the reaction conditions, adenine can thus be considered as an organoinitiator or an organocatalyst for the ring-opening polymerization of lactide.

Design and Synthesis of Novel Kinase Inhibitors for the Treatment of Chronic Respiratory Diseases

In 2017, Chronic Respiratory Diseases accounted for almost four million deaths worldwide. Unfortunately, current treatments are not definitive for such diseases. This unmet medical need forces the scientific community to increase efforts in the identification of new therapeutic solutions. PI3K delta plays a key role in mechanisms that promote airway chronic inflammation underlying Asthma and COPD. The first part of this project was dedicated to the identification of novel PI3K delta inhibitors. A first SAR expansion of a Hit, previously identified by a HTS campaign, was carried out. A library of 43 analogues was synthesised taking advantage of an efficient synthetic approach. This allowed the identification of an improved Hit of nanomolar enzymatic potency and moderate selectivity for PI3K delta over other PI3K isoforms. However, this compound exhibited low potency in cell-based assays. Low cellular potency was related to sub optimal phys-chem and ADME properties. The analysis of the X-ray crystal structure of this compound in human PI3K delta guided a second tailored SAR expansion that led to improved cellular potency and solubility. The second part of the thesis was focused on the rational design and synthesis of new macrocyclic Rho-associated protein kinases (ROCKs) inhibitors. Inhibition of these kinases has been associated with vasodilating effects. Therefore, ROCKs could represent attractive targets for the treatment of pulmonary arterial hypertension (PAH). Known ROCK inhibitors suffer from low selectivity across the kinome. The design of macrocyclic inhibitors was considered a promising strategy to obtain improved selectivity. Known inhibitors from literature were evaluated for opportunities of macrocyclization using a knowledge-based approach supported by Computer Aided Drug Design (CADD). The identification of a macrocyclic ROCK inhibitor with enzymatic activity in the low micro molar range against ROCK II represented a promising result that validated this innovative approach in the design of new ROCKs inhibitors.