Development of diphenylmethylpiperazine hybrids of chloroquinoline and triazolopyrimidine using Petasis reaction as new cysteine proteases inhibitors for malaria therapeutics

Malaria is a widespread infectious disease, causing nearly 247 million cases in 2021. The absence of a broadly effective vaccine and rapidly decreasing effectiveness of most of the currently used antimalarials are the major challenges to malaria eradication efforts. To design and develop novel antimalarials, we synthesized a series of 4,7-dichloroquinoline and methyltriazolopyrimidine analogues using a multi-component Petasis reaction. The synthesized molecules (11-31) were screened for in-vitro antimalarial activity against drug-sensitive and drugresistant strains of Plasmodium falciparum with an IC50 value of 0.53 & mu;M. The selected compounds were screened to evaluate in-vitro and in-silico enzyme inhibition efficacy against two cysteine proteases, PfFP2 and PfFP3. The compounds 15 and 17 inhibited PfFP2 with an IC50 = 3.5 and 4.8 & mu;M, respectively and PfFP3 with an IC50 = 4.9 and 4.7 & mu;M, respectively. Compounds 15 and 17 were found equipotent against the Pf3D7 strain with an IC50 value of 0.74 & mu;M, whereas both were displayed IC50 values of 1.05 & mu;M and 1.24 & mu;M for the PfW2 strain, respectively. Investigation of effect of compounds on parasite development demonstrated that compounds were able to arrest the growth of the parasites at trophozoite stage. The selected compounds were screened for in-vitro cytotoxicity against mammalian lines and human red-blood-cell (RBC), which demonstrated no significant cytotoxicity associated with the molecules. In addition, in silico ADME prediction and physiochemical properties supported the drug-likeness of the synthesized molecules. Thus, the results highlighted the diphenylmethylpiperazine group cast on 4,7-dichloroquinoline and methyltriazolopyrimidine using Petasis reaction may serve as models for the development of new antimalarial agents.

Automated summary

Malaria is a widespread infectious disease that caused nearly 247 million cases in 2021. The lack of an effective vaccine and declining effectiveness of current antimalarials pose major challenges to eradicating malaria. In this study, a series of 4,7-dichloroquinoline and methyltriazolopyrimidine analogues were synthesized to develop novel antimalarials. These synthesized molecules were found to have potent in-vitro antimalarial activity and inhibit cysteine proteases. They also demonstrated the ability to arrest the growth of parasites without significant cytotoxicity. Overall, these findings suggest the potential of these molecules as new antimalarial agents.