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Malaria is an infectious disease caused by protozoan parasites belonging to the Plasmodium species. The disease has been a major cause of mortality and morbidity, especially in populations of African and South- East Asian countries. A well-developed treatment regimen including the artemisinins as a potent antimalarial and other safety preventive measures have played a major role in reducing global burden of malaria over the years. However, recent reports of drug resistance against the artemisinins should be a wakeup call, for the artemisinins have been the mainstay towards the treatment of the disease in recent past. There is a need for newer antimalarials that can be active on more than one stage of the parasite life cycle. These may be complementary to the artemisinins and may also help in keeping a check on the menace of drug resistance. The current review focuses on clinical drug candidates with activity against more than one stages of the malarial parasite life cycle. [ABSTRACT FROM AUTHOR]

Abstract TLR9 is one of the major innate immune receptors expressed in the endosomes of pDCs and B cells in humans. Aberrant TLR9 activation is implicated in several autoimmune and metabolic disorders as well as in sepsis, making this receptor an important therapeutic target, though specific TLR9 antagonists are yet to be available for clinical use. Here we elucidate the importance of specific physiochemical properties through substitution patterns in quinazoline scaffold to achieve potent hTLR9 inhibition at < 50 nM as well as > 600 fold selectivity against hTLR7, another closely related TLR that shares downstream signaling with TLR9 but plays distinct roles in physiology and pathology. Assays were performed using hPBMC and reporter cell lines. Favorable in vitro ADME profile, pharmacokinetics as well as validation in a clinically relevant in vivo TLR9-inhibition efficacy model in mice establish these novel TLR9-antagonists as candidate therapeutic agents in relevant clinical contexts. Graphical abstract Image 1 Highlights • Substitutions in quinazoline that influence potency and specificity for hTLR9. • Favourable in vitro ADME and pharmacokinetics in rodent model. • In vivo TLR9-inhibition efficacy was investigated in a rodent model. • Development of potent TLR9 antagonist with excellent selectivity against TLR7. [ABSTRACT FROM AUTHOR]