Synthesis and antimalarial activity of sulfonamide-attached coumarin-[1,2,3]-triazoles

Drug resistance in malaria parasites is one of the major stumbling blocks hindering the goal of malaria elimination. One of the major strategies to counter drug resistance is the development of new potent antimalarial drugs. In the present study, a series of novel sulfonamide based coumarin-[1,2,3]-triazole conjugates have been synthesized via Huisgen reaction between azidosulfonamides and 4-hydroxy- or 7-hydroxymethylcoumarinoalkynes. All the compounds have been characterized spectroscopically and screened for their in vitro antimalarial activity against P. falciparum 3D7 strain. Out of the twenty five synthesized compounds, four compounds displayed significant activity (IC50 <10 µM) with the most active compound having an IC50 of 3.64 µM.

Synthesis and antimalarial activity of sulfonamide-attached coumarin-[1,2,3]-triazoles

1545-1555Drug resistance in malaria parasites is one of the major stumbling blocks hindering the goal of malaria elimination. One of the major strategies to counter drug resistance is the development of new potent antimalarial drugs. In the present study, a series of novel sulfonamide based coumarin-[1,2,3]-triazole conjugates have been synthesized via Huisgen reaction between azidosulfonamides and 4-hydroxy- or 7-hydroxymethylcoumarinoalkynes. All the compounds have been characterized spectroscopically and screened for their in vitro antimalarial activity against P. falciparum 3D7 strain. Out of the twenty five synthesized compounds, four compounds displayed significant activity (IC50 50 of 3.64 µM

Methylene blue induced morphological deformations in Plasmodium falciparum gametocytes: implications for transmission-blocking

Abstract Background Malaria remains a global health problem despite availability of effective tools. For malaria elimination, drugs targeting sexual stages of Plasmodium falciparum need to be incorporated in treatment regimen along with schizonticidal drugs to interrupt transmission. Primaquine is recommended as a transmission blocking drug for its effect on mature gametocytes but is not extensively utilized because of associated safety concerns among glucose-6-phosphate dehydrogenase (G6PD) deficient patients. In present work, methylene blue, which is proposed as an alternative to primaquine is investigated for its gametocytocidal activity amongst Indian field isolates. An effort has been made to establish Indian field isolates of P. falciparum as in vitro model for gametocytocidal drugs screening. Methods Plasmodium falciparum isolates were adapted to in vitro culture and induced to gametocyte production by hypoxanthine and culture was enriched for gametocyte stages using N-acetyl-glucosamine. Gametocytes were incubated with methylene blue for 48 h and stage specific gametocytocidal activity was evaluated by microscopic examination. Results Plasmodium falciparum field isolates RKL-9 and JDP-8 were able to reproducibly produce gametocytes in high yield and were used to screen gametocytocidal drugs. Methylene blue was found to target gametocytes in a concentration dependent manner by either completely eliminating gametocytes or rendering them morphologically deformed with mean IC50 (early stages) as 424.1 nM and mean IC50 (late stages) as 106.4 nM. These morphologically altered gametocytes appeared highly degenerated having shrinkage, distortions and membrane deformations. Conclusions Field isolates that produce gametocytes in high yield in vitro can be identified and used to screen gametocytocidal drugs. These isolates should be used for validation of gametocytocidal hits obtained previously by using lab adapted reference strains. Methylene blue was found to target gametocytes produced from Indian field isolates and is proposed to be used as a gametocytocidal adjunct with artemisinin-based combination therapy. Further exploration of methylene blue in clinical studies amongst Indian population, including G6PD deficient patients, is recommended