Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[34-d]-pyrimidinodiones as new antiplasmodial compounds

BACKGROUND Malaria is responsible for 429,000 deaths per year worldwide, and more than 200 million cases were reported in 2015. Increasing parasite resistance has imposed restrictions to the currently available antimalarial drugs. Thus, the search for new, effective and safe antimalarial drugs is crucial. Heterocyclic compounds, such as dihydropyrimidinones (DHPM), synthesised via the Biginelli multicomponent reaction, as well as bicyclic compounds synthesised from DHPMs, have emerged as potential antimalarial candidates in the last few years. METHODS Thirty compounds were synthesised employing the Biginelli multicomponent reaction and subsequent one-pot substitution/cyclisation protocol; the compounds were then evaluated in vitro against chloroquine-resistant Plasmodium falciparum parasites (W2 strain). Drug cytotoxicity in baseline kidney African Green Monkey cells (BGM) was also evaluated. The most active in vitro compounds were evaluated against P. berghei parasites in mice. Additionally, we performed an in silico target fishing approach with the most active compounds, aiming to shed some light into the mechanism at a molecular level. RESULTS The synthetic route chosen was effective, leading to products with high purity and yields ranging from 10-84%. Three out of the 30 compounds tested were identified as active against the parasite and presented low toxicity. The in silico study suggested that among all the molecular targets identified by our target fishing approach, Protein Kinase 3 (PK5) and Glycogen Synthase Kinase 3β (GSK-3β) are the most likely molecular targets for the synthesised compounds. CONCLUSIONS We were able to easily obtain a collection of heterocyclic compounds with in vitro anti-P. falciparum activity that can be used as scaffolds for the design and development of new antiplasmodial drugs.

Spectroscopy Studies, X-Ray Crystallography, and Antitumor Evaluation of the Behavior of Reactions of Bisdimedone Derivatives with Malononitrile or with Benzylidenemalononitile in Ethanolic Piperidine.

A simple, environmentally acceptable, a one-pot method, which is efficient, inexpensive, and rapid, afforded excellent yields of the 4H-chromeme derivatives 5 and 6 from a three-component reaction of dimedone, arylaldehdes 2a-b, and malononitrile and a two-component reaction of bisdimedones 3a-b and malononitrile, respectively. Refluxing ethanolic piperidine was used as the catalyst for the 10-min reactions. A one-pot reaction of benzylidenemalononitrile, instead of malononitrile, with bisdimedones 3a-b, using the aforementioned reaction, also provided the 4H-chromene derivative 5 in excellent yield. The structures of the newly synthesized compounds were elucidated by elemental analyses, X-ray crystallography, and a variety of spectroscopic methods, including proton and carbon nuclear magnetic resonance spectroscopy (1H-NMR and 13C-NMR, respectively), correlation spectroscopy (COSY), heteronuclear single quantum coherence spectroscopy (HSQC), heteronuclear multiple-bond correlation spectroscopy (HMBC), and mass spectrometry (MS). The inhibitory effects of the 4H-chromeme derivatives 5 and 6 on the in vitro growth of human tumor cell and normal cell lines were greater than that of the reference drug doxorubicin.