Browsing by Author "Ding, Sha"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Mosquito Acetylcholinesterase as a Target for Novel Phenyl-Substituted Carbamates
    Mutunga, James M.; Ma, Ming; Chen, Qiao-Hong; Hartsel, Joshua A.; Wong, Dawn M.; Ding, Sha; Totrov, Maxim M.; Carlier, Paul R.; Bloomquist, Jeffrey R. (MDPI, 2019-04-28)
    New insecticides are needed for control of disease-vectoring mosquitoes and this research evaluates the activity of new carbamate acetylcholinesterase (AChE) inhibitors. Biochemical and toxicological characterization of carbamates based on the parent structure of terbam, 3-tert-butylphenyl methylcarbamate, was performed. In vitro enzyme inhibition selectivity (Anopheles gambiae versus human) was assessed by the Ellman assay, as well as the lethality to whole insects by the World Health Organization (WHO) paper contact assay. Bromination at the phenyl C6 position increased inhibitory potency to both AChEs, whereas a 6-iodo substituent led to loss of potency, and both halogenations caused a significant reduction of mosquitocidal activity. Similarly, installation of a hexyl substituent at C6 drastically reduced inhibition of AgAChE, but showed a smaller reduction in the inhibition of hAChE. A series of 4-carboxamido analogs of the parent compound gave reduced activity against AgAChE and generally showed more activity against hAChE than AgAChE. Replacement of the 3-t-buyl group with CF3 resulted in poor anticholinesterase activity, but this compound did have measurable mosquitocidal activity. A series of methyl- and fluoro- analogs of 3-trialkylsilyl compounds were also synthesized, but unfortunately resulted in disappointing activity. Finally, a series of sulfenylated proinsecticides showed poor paper contact toxicity, but one of them had topical activity against adult female Anopheles gambiae. Overall, the analogs prepared here contributed to a better understanding of carbamate structure–activity relationships (SAR), but no new significant leads were generated.
  • Thumbnail Image
    Novel Antimalarial Compounds from the Optimization of the Malaria Box
    Ding, Sha (Virginia Tech, 2020-08-27)
    Malaria continues to threaten human beings, causing a staggering number of more than 400,000 deaths each year. Although effective treatment and prevention methods are available, rapidly emerging resistance towards existing drugs is of great concern, and the need for novel antimalarial compounds are still urgent. The Malaria Box lead molecules MMV008138 and MMV665831 are promising in this regard, due to their apparently novel antimalarial mechanisms of action. The target of MMV008138 is the PfIspD enzyme in the MEP pathway, which is absent in humans. This difference makes the PfIspD a great target. However, while MMV008138 shows potency against Plasmodium falciparum-infected human erythrocytes in vitro, no efficacy was observed in a humanized mouse model or a P. berghei infected mouse in vivo. In order to block potential metabolic spots and to probe for steric demand, a series of analogous featuring C1-deuteration, methyl substitution on B- and C-ring, and an ethylene bridge were prepared. The effect of various substitution on the tetrahydro-β-carboline conformation and D-ring orientation was studied. In the course of preparing the C1-Me analog of MMV008138 featuring 2',4'- dichloro substitution, unexpected ring-expanded azepane products were isolated. Later it was found that the desired product could be isolated when the imine formed was treated with acid at lower temperature. Other intermediates possessing a 2ʹ- substituent were also isolated under the low temperature acid treatment protocol, which upon heating in acid gave the ring-expanded azepane we initially isolated. A mechanism was proposed to account for the formation of the azepane as well as other intermediates. The driving force of the expansion reaction was explored, and the hypothesis that the steric interaction between the 2ʹ-substituent and the C1-Me was supported via DFT calculation and conformational analysis. MMV665831 is another potent hit from the Malaria Box, and it appears to inhibit the hemoglobin endocytosis process of P. falciparum. The structure–activity relationship of MMV665831 was studied with analogues featuring modifications on C2-benzamide, C3-ester, C-7 phenol, as well as the phenolic Mannich base moiety. Modifications at phenolic Mannich base moiety leads to the discovery of an analogue that is twice as potent toward cultured P. falciparum compared to MMV665831. We were worried the phenolic Mannich base moiety might act as the precursor of toxic quinone methide intermediates, and designed two analogs to block this potential toxicophore. Although the modification resulted in reduced potency, this result proved that the potency of MMV665831 does not stem from the formation of quinone methides. Unfortunately, MMV665831 did not reduce parasitemia in P. berghei- infected mice. Fast hepatocyte metabolism was observed for MMV665831, and the loss of in vivo efficacy was discussed in comparison with other phenolic Mannich bases with similar hepatocyte stability.