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.

Synthesis and in-vitro screening of 3,4-dihydropyrimidin-2(1H)-one derivatives for antihypertensive and calcium channel blocking activity.

Pyrimidine plays a significant role among other heterocycles. From the literature survey, in recent years the design of 3,4-dihydropyrimidin-2(1H)-ones nucleus have been attracted for considerable interest because of their therapeutic and pharmacological properties. Pyrimidine nucleus was synthesized by Biginelli reaction. This product was subjected for alkaline ester hydrolysis and these derivatives on treatment with thionyl chloride and substitution by different secondary amines produced final desired compounds. The remaining compounds have been synthesized by above method. The purity of the compounds has been checked by TLC monitoring and the conformation of structure was confirmed by different spectra like UV, IR, NMR, Mass etc. The in-vitro antihypertensive and calcium channel blocking activity have been done by IC50 measurement method with nifedipine as standard.

A new green room temperature ionic liquid catalyzes synthesis of monastrol and its derivatives through Biginelli reaction / 第二军医大学学报

Objective To explore an easily-controllable, environmentally-friendly method for synthesizing monastrol and its derivatives. Methods Monastrol and its derivatives were synthesized using (substituted) benzaldehyde, ethyl acetoacetate and thiourea (or urea) as the material through a Biginelli reaction catalyzed by green room temperature ionic liquid 1-butyl-3- methylimidazolium-L-camphorsulfonate under microwave irradiation without solvent. Results The green room temperature ionic liquid 1-butyl-3-methylimidazolium-L-camphorsulfonate catalyzed Biginelli reaction in obtaining the title compound under microwave irradiation without solvent. The process was easy to operate, time saving and environmentally-friendly. Conclusion Microwave-accelerated solvent-free Biginelli reaction using green room temperature ionic liquid 1-butyl-3-methylimidazolium-L- camphorsulfonate as catalyst is a convenient and environmentally-friendly method for synthesizing monastrol and its derivatives.

A new green room temperature ionic liquid catalyzes synthesis of monastrol and its derivatives through Biginelli reaction / 第二军医大学学报

Objective To explore an easily-controllable, environmentally-friendly method for synthesizing monastrol and its derivatives. Methods Monastrol and its derivatives were synthesized using (substituted) benzaldehyde, ethyl acetoacetate and thiourea (or urea) as the material through a Biginelli reaction catalyzed by green room temperature ionic liquid 1-buty-3- methylimidazolium-L-camphorsulfonate under microwave irradiation without solvent. Results The green room temperature ionic liquid 1-buty-3-methylimidazolium-L-camphorsulfonate catalyzed Biginelli reaction in obtaining the title compound under microwave irradiation without solvent. The process was easy to operate, time saving and environmentally-friendly. Conclusion Microwave-accelerated solvent-free Biginelli reaction using green room temperature ionic liquid 1-buty-3-methylimidazolium-L- camphorsulfonate as catalyst is a convenient and environmentally-friendly method for synthesizing monastrol and its derivatives.