<p> </p>
<p>Infectious diseases caused by bacteria, fungi, and
plasmodium parasites are a huge global health problem which ultimately leads to
millions of deaths annually. The emergence of
strains that exhibit resistance to nearly every class of antimicrobial agents,
and the inability to keep up with these resistance trends has brought to the
fore the need for new therapeutic agents (antibacterial, antifungal, and
antimalarial) with novel scaffolds and functionalities capable of targeting microbial
resistance. A novel class of compounds featuring an aryl isonitrile moiety has
been discovered that exhibits potent inhibitory activity against several
clinically relevant strains of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Synthesis, structure-activity relationship (SAR) studies, and
biological investigations have led to lead molecules that exhibit anti-MRSA inhibitory
activity as low as 1 – 2
µM. The most potent compounds have
also been shown to have low toxicity against mammalian cells and exhibit <i>in
vivo</i> efficacy in MRSA skin and thigh infection mouse models.</p>
<p>The
novel aryl isonitriles have also been evaluated for antifungal activity. This study
examines the SAR of aryl isonitrile compounds and showed the isonitriles as
compounds that exhibit broad spectrum antifungal activity against species of <i>Candida</i>
and <i>Cryptococcus</i>. The most potent derivatives are capable of inhibiting
growth of these pathogens at concentrations as low as 0.5 µM. Notably, the most active compounds exhibit
excellent safety profile and are non-toxic to mammalian cells up to 256 µM.</p>
<p>Beyond the antibacterial and antifungal
activities, structure-antimalarial relationship analysis of over 40 novel aryl
isonitrile compounds has established the importance of the isonitrile
functionality as an important moiety for antimalarial activity. Of the many
isonitrile compounds exhibiting potent antimalarial activity, two have emerged
as leads with activity comparable to that of Artemisinin. The SAR details
presented in this study will prove essential for the development new aryl
isonitrile analogues to advance them to the next step in the antimalarial drug
discovery process.</p>
<p>17-nor-Excelsinidine,
a zwitterion monoterpene indole alkaloid isolated from <i>Alstonia scholaris</i> is a subject of synthetic scrutiny. This is
primarily due to its intriguing chemical structure which includes a bridged
bicyclic ammonium moiety, and its anti-adenovirus and anti-HSV activity. Herein
we describe a six-step total synthesis of (±)-17-nor-Excelsinidine
from tryptamine. Key to the
success of this synthesis is the use of palladium-catalyzed carbonylative heck
lactamization methodology which built the 6, 7-membered ring lactam in one
step. The resulting pentacyclic product, beyond facilitating the easy access to
(±)-17-nor-Excelsinidine,
could also serve as a precursor to other related indole alkaloids.</p>
<br>
<p> </p>
<p></p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8018465 |
| Date | 15 May 2019 |
| Creators | Kwaku Kyei-Baffour (6616715) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/DEVELOPMENT_OF_ARYL_ISONITRILES_AS_ANTIMICROBIAL_AGENTS_AND_TOTAL_SYNTHESIS_OF_17-NOR-EXCELSINIDINE/8018465 |
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