In this work, we performed the design, synthesis, and the structure-activity relationship studies of 13 new derivatives of thieno[2,3-b]pyridine. These derivatives were prepared in high yields (96-70%) and their structures were elucidated by IR, (1)H, (13)C NMR, and MS. The biological results showed some derivatives as antiparasitic agents against Giardia lamblia. Computational analysis of HOMO and LUMO energy, HOMO orbital coefficient distribution, electrostatic potential map, dipole moment, and density HOMO was performed to gain insight into the SAR aspects. This study pointed the p-methoxy substituted derivative as a leading compound for the development of new microbicidal medicines based on thieno[2,3-b]pyridine analogs.

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Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) Plasmodium falciparum clone strain and in vivo against Plasmodium berghei-infected mouse model. Among the quinoline derivatives, new hybrids between chloroquine and sulfadoxine were designed, which gave rise to an important prototype that was more active than both chloroquine and sulfadoxine. Hybrids between chloroquine–atorvastatin and primaquine–atorvastatin were also synthesized and shown to be more potent than the parent drugs alone. Additionally, among the quinoline derivatives, new mefloquine derivatives were synthesized. Among the non-quinoline derivatives, we obtained excellent results with the triazolopyrimidine nucleus, which gave us prototype I that inspired the synthesis of new heterocycles. The pyrazolopyrimidine derivatives stood out as non-quinoline derivatives that are potent inhibitors of the P. falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. We also examined the pyrazolopyridine and pyrazolopyrimidine nuclei.

Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost-effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine-resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3-triazole derivatives against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum has been reported in the literature. To enhance the anti-P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline-1H-1,2,3-triazole hybrids with different substituents in the 4-positions of the 1H-1,2,3-triazole ring, which were assayed against the W2-chloroquine-resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine-resistant, with IC50 values ranging from 1.4 to 46 μm. None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound (11).