Further Exploring the Structure Activity Relationship (SAR) of MMV008138 and MMV1803522

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Virginia Tech


The war between human and malaria has never stopped, and the development and application of antimalarial drugs has not eradicated this terrible disease. To fight drug-resistant malaria, many leads have been studied over the years. (1S,3R)-MMV008138 and MMV1803522 are two compounds that have been studied in the Carlier Group. My research focused on the structural variation of each of these compounds, in the hope that greater potency could be realized. Chapter 2 describes my work on (1S,3R)-MMV008138, which inhibits the enzyme PfIspD in the methylerythritol phosphate (MEP) pathway. This compound shows good in vitro potency against the drug resistant Dd2 strain of Plasmodium falciparum. However, this lead showed no activity in mouse models. This lack of activity may be due to poor metabolic stability of the compound. However, a significant increase in in vitro potency could also improve in vivo activity. Towards that end, I focused on further variation of the D-ring and A-rings. With the regard to the D-ring, we made five analogs of MMV008138 that replaced the 2,4-dichlorophenyl ring with dihalogenated thiophen-3-yl and thiophen-2-yl rings. We also explored the effect of installing a cyano group on the A-ring of MMV008138. Unfortunately, none of these new compounds were potent growth inhibitors of Dd2 strain P. falciparum. We conclude that the lead goes into a well-defined pocket within the PfIspD enzyme that only accommodates 2,4-dihalogenated phenyl D-rings. This pocket also cannot accept any substitution larger than F on the A-ring. Interestingly, the crystal structure of 5-cyano-substituted MMV008138 was obtained ((±)-2-50c). This is the first compound out of more than 100 analogs of MMV008138 family to be amenable to crystallization. The solid state conformation of the (±)-2-50c revealed that the C3-carboxyl group was in a pseudoequatorial orientation, and the C1-aryl group was thus in a pseudoaxial orientation. 1H NMR spectroscopic studies in CD3OD-D2O were carried out to determine the solution conformation. As expected from previous studies of ester derivatives of MMV008138, these studies indicated that in solution, 2-5 would adopt both the C3-carboxyl pseudoequatorial and pseudoaxial conformations. In Chapter 3, I describe the synthesis of analogs of the antimalarial drug candidate MMV1803522. This β-carboline-3-carboxamide shows good in vitro growth inhibition potency of Dd2 strain P. falciparum, operating by a still unknown mechanism. To investigate the pharmacophore of this lead, I first sought to determine whether the pyridine N (i.e. N2) of the β-carboline was important for in vitro potency. I prepared series of carbazole analogs of MMV1803522, which replace N2 with a CH. These compounds potently inhibited the growth of Dd2 strain P. falciparum. These results suggest that N2 of MMV1803522 is not involved in any energetically significant interactions with its target protein. To further identify the pharmacophore, we prepared truncated analogs lacking the A- and B- rings (biphenyl analogs), and tricyclic analogs that feature a reversed indole moiety. Unfortunately, the biphenyl analogs and reversed indole analogs show no growth inhibition at 10,000 nM the highest concentration tested. Lastly, I describe analogs of MMV1803522 in which the 3,4-dichlorophenyl ring of MMV1803522 was replaced with halogenated thiophene. This substitution was tolerated, but compounds were roughly half as potent as MMV1803522.



Malaria, Plasmodium, Malaria Box, MMV008138, MMV1803522, TCMDC140230, MEP pathway, structure-activity relationship, Carbazole, Pictet-Spengler reaction, Suzuki coupling reaction