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Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life ( t 1/2 ) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t 1/2 . UCB7362 is estimated to achieve 9 log 10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.

Various aryl Fischer carbenes reacted with alkynes having adjacent acyloxy or carbonate groups to regioselectively deliver 3-substituted 1-indanones. The acyloxy or carbonate group probably coordinates with the Cr metal to give a tetra-coordinated chromium complex forming a six-membered ring that retards CO insertion for ketene formation, which is required for benzannulation. Alternatively, the ortho position aryl ring attack results in pentannulation, providing regioselectively 3-substituted 1-indanones. The method is extended to the synthesis of the core structure of 3- epi -mutisianthol.

The first stereoselective total synthesis of (-)-asteriscunolide C has been accomplished in 12 steps in a 16% overall yield. The key step is the conversion of a 12-membered to a strained 11-membered ring with one Z- and two E-double bonds employing a late stage ring-closing metathesis.

A general, efficient, and common strategy for the synthesis of (-)-juglomycin A, (+)-kalafungin, (+)-frenolicin B, and (+)-deoxyfrenolicin is reported here. The strategy involves the synthesis of a key building block alkyne from a cheap chiral pool material, D-glucono-δ-lactone, Dötz benzannulation, oxa-Pictet-Spengler reaction, and H(2)SO(4)-mediated epimerization.

A stereoselective synthesis of (-)-1-epi-ventiloquinone L and (+)-ventiloquinone L, the monomeric unit of cardinalin 3 has been described. The synthesis is completed in 7 steps with 10.5% and 13% overall yields for (-)-1-epi-ventiloquinone L and (+)-ventiloquinone L respectively. The key steps involve Dötz benzannulation of carbene 5 with alkyne 6 to give a substituted naphthalene moiety and oxa-Pictet-Spengler reaction to install the 1,3-dimethylpyran moiety.

Coumarino acid hydrazides and acid hydrazide of 2-oxy 3, 5, 6-trichloropyridine were prepared in two steps. These acid hydrazides on condensation with Acetonyl acetone i.e. 2,5-hexanedione yields new pyrroles. These pyrroles showed good to moderate antimicrobial activities against Alternaria brassicicola, Aspergillus niger, E. coli and Lactobacillus.