Application of “Hydrogen-Bonding Interaction”
in Drug Design. Part 2: Design, Synthesis, and Structure–Activity
Relationships of Thiophosphoramide Derivatives as Novel Antiviral
and Antifungal Agents
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Abstract
On
the basis of the structure of natural product harmine, lead
compound <b>18</b>, and the structure of compounds in part 1,
a series of thiophosphoramide derivatives <b>1</b>–<b>17</b> were designed and synthesized from various amines in one
step. Their antiviral and antifungal activities were evaluated. Most
of the compounds showed significantly higher antiviral activity against
tobacco mosaic virus (TMV) than commercial virucide ribavirin. Compound
(<i>R</i>,<i>R</i>)-<b>17</b> showed the
best anti-TMV activity <i>in vitro</i> (70%/500 μg/mL
and 33%/100 μg/mL) and <i>in vivo</i> (inactivation
effect, 68%/500 μg/mL and 30%/100 μg/mL; curative effect,
64%/500 μg/mL and 31%/100 μg/mL; protection effect, 66%/500
μg/mL and 31%/100 μg/mL), which is higher than that of
ningnanmycin and lead compound <b>18</b>. The antiviral activity
of (<i>R</i>,<i>R</i>)-<b>17</b>·HCl
is about similar to that of (<i>R</i>,<i>R</i>)-<b>17</b>. However, the antifungal activity of (<i>R</i>,<i>R</i>)-<b>17</b>·HCl against Puccinia sorghi is slightly lower than that of (<i>R</i>,<i>R</i>)-<b>17</b>. The systematic study
provides compelling evidence that these simple thiophosphoramide compounds
could become efficient antiviral and antifungal agents