Novel Quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione Derivatives Against Chloroquine-resistant Plasmodium falciparum.

Abstract

AIMS\nObtaining new quinolinyl-pyrrolopyrimidinone derivatives against chloroquine-resistant Plasmodium falciparum. Background: Malaria is currently considered one of the most serious public health problems, with an estimated 219 million new cases in 2017. The number of drugs currently available for the treatment of malaria is limited, and P. falciparum, responsible for the most severe cases, has become increasingly resistant to the available drugs. One alternative to overcome parasite drug resistance to quinoline derivatives is the generation of hybrid compounds by adding different moieties to the quinoline nucleus. We have demonstrated the importance of some new compounds against P. falciparum based on molecular hybrids. Objective: This work DHPMs were combined with the quinoline nucleus to obtain new quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione compounds with improved antiplasmodial activity as well as decreased cytotoxicity. Nineteen quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives connected by a linker group to quinoline ring moieties with different substituents were synthesized and assayed against P. falciparum. Method: The compounds was obtained via the multicomponent Biginelli reaction (scheme 1) using aromatic aldehydes (4), urea (5) and ethyl 4-chloroacetoacetate (6) as building blocks in ethanol with HCl as catalyst. Result:Among the synthetised compounds, the derivatives with two methylene carbon that connecting the quinoline with the pyrimidinone moieties showed the best activity accompanied by low cytotoxicity. The derivative without substituents on the aromatic ring and the derivative with a chlorine group at 4- position provided the best results, with IC50 = 1.15 µM and 1.5 µM, respectively. Conclusion: Nineteen new quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-diones were synthesized. The low toxicity coupled with the IC50 values of the compounds provides support for further structural modifications aimed at improving the antiplasmodial activity so that improved IC50 and MDL50 values are achieved, allowing the development of new derivatives for use in malaria therapy. Other: Given the widespread resistance to virtually all existing drugs, the emergence of a new class of molecules with antiplasmodial activity obtained through simple synthetic protocols is promising.