Helioxanthin

Drug resistance to commercially available antimalarials is a major obstacle in malaria control and elimination, creating the need to find new antiparasitic compounds with novel mechanisms of action. The success of kinase inhibitors for oncological treatments has paved the way for the exploitation of protein kinases as drug targets in various diseases, including malaria. Casein kinases are ubiquitous serine/threonine kinases involved in a wide range of cellular processes such as mitotic checkpoint signaling, DNA damage response, and circadian rhythm. In Plasmodium , it is suggested that these protein kinases are essential for both asexual and sexual blood-stage parasites, reinforcing their potential as targets for multi-stage antimalarials. To identify new putative Pf CK2α inhibitors, we utilized an in silico chemogenomic strategy involving virtual screening with docking simulations and quantitative structure-activity relationship predictions. Our investigation resulted in the discovery of a new quinazoline molecule ( 542 ), which exhibited potent activity against asexual blood stages and a high selectivity index (>100). Subsequently, we conducted chemical-genetic interaction analysis on yeasts with mutations in casein kinases. Our chemical-genetic interaction results are consistent with the hypothesis that 542 inhibits yeast Cka1, which has a hinge region with high similarity to Pf CK2α. This finding is in agreement with our in silico results suggesting that 542 inhibits Pf CK2α via hinge region interaction.

The helioxanthin derivative 4-(4-methoxyphenyl)thieno[2,3-b:5,4-c']dipyridine-2-carboxamide (TH) is a low-molecular-weight compound that was identified through screening for osteogenic compounds that enhance the activity of mouse preosteoblastic MC3T3-E1 cells. In the present study, we found that TH suppressed osteoclast differentiation.

Using the hematopoietic stem cells of ddY mice, TH was added to the culture in the experimental group, and the number of osteoclasts was measured with rhodamine phalloidin staining and TRAP staining. In osteo assay, bone resorption area was compared by the von Kossa staining.

Specifically, TH inhibited the cyclic guanosine monophosphate (cGMP)-degrading activity of phosphodiesterase (PDE), promoted nitric oxide (NO) production, and dose-dependently suppressed osteoclast differentiation in an osteoclast formation culture of mouse bone marrow cells. The NO-competitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) attenuated the suppressive activity of TH on osteoclast differentiation. Conclusion: Given the previously reported suppressive action of cGMP on osteoclastogenesis, our data suggest that TH negatively impacts osteoclast differentiation at least to some extent by stimulating NO production and inhibiting PDE activity, both of which lead to the upregulation of intracellular cGMP. This study supports the potential use of TH as a novel antiosteoporotic reagent that not only stimulates bone formation but also inhibits bone resorption.