Solid-phase synthesis and antibacterial activity of hydroxycinnamic
acid amides and analogues against methicillin-resistant
Staphylococcus aureus and vancomycin-resistant S. aureus
Boon-ek Yingyongnarongkul,
a,
*
Nuttapon Apiratikul,
a
Nuntana Aroonrerk
b
and
Apichart Suksamrarn
a
a
Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkapi, Bangkok 10240, Thailand
b
Department of Stomatology, Faculty of Dentistry, Srinakharinwirot University, Wadhana, Bangkok 10110, Thailand
Received 9 May 2006; revised 9 August 2006; accepted 11 August 2006
Available online 30 August 2006
Abstract—A library of hydroxycinnamic acid amides (HCAAs) and analogues were synthesized using solid-phase synthesis tech-
nique. These compounds were screened for antibacterial against methicillin-resistant Staphylococcus aureus (MRSA) (11 strains)
and vancomycin-resistant S. aureus (VRSA) (4 strains). Dihydrocaffeoyl analogues showed activity against VRSA which were better
than the reference drugs, vancomycin and oxacillin. These compounds also exhibited antibacterial activity against MRSA, which
were more potent than oxacillin.
Ó 2006 Elsevier Ltd. All rights reserved.
The rapid incidence of multiple drug-resistant Gram-po-
sitive bacteria requires an urgent discovery of novel
active agents against these pathogens.
1
Methicillin-resis-
tant Staphylococcus aureus (MRSA) is still one of the
most serious issues in public health in developed coun-
tries. It does not only have a high incidence but it has
also become resistant to almost all the currently avail-
able antibiotics.
2
The rapid development of pathogens
resistant to vancomycin, the last resort antibiotic against
MRSA, has been reported.
3
This development creates a
new demand for alternative antibiotics, the structure of
which differs from conventional antibiotics, against van-
comycin-resistant S. aureus (VRSA) as well as MRSA.
Hydroxycinnamic acid amides (HCAAs) are di- and
polyamines conjugated to various phenolic acids, cou-
maric, ferulic, and caffeic acids (Fig. 1). These classes
of compounds are widely distributed in higher plants.
The roles of HCAAs in plants are not clear. Many stud-
ies have suggested that these compounds might play an
important role in the chemical defense of plants against
fungal and bacterial pathogens.
4,5
Our program is aimed to search for bioactive natural
products as well as to investigate a natural molecular
template for drug discovery to treat human diseases.
HCAAs are molecules of our interest and we have
hypothesized that this class of compounds might also
have activity against human pathogens. The synthesis
of hydroxycinnamic acid amide analogues with different
polyamines has been reported. However, the synthesis of
HCAAs in solution is a laborious task since it involves
extensive use of protective group strategy
5
and requires
tedious purification steps due to the polarity of the com-
pounds. Solid-phase organic synthesis has emerged as a
powerful technology with several advantages including
simplification of reaction procedures, easy separation
of supported species and products, and application to
automation system.
6
We report here the solid-phase syn-
thesis of HCAAs with different diamines and coumaroyl
analogues and related aromatic carboxylic acids. The
synthesized compounds have been evaluated against
MRSA and VRSA strains.
Our approach to generate a HCAAs library via solid-
phase parallel synthesis is shown in Scheme 1.
7
Wang
resin was prepared by shaking Merrifield resin with
4-hydroxybenzyl alcohol in the presence of K
2
CO
3
and
KI at room temperature for overnight. Reaction of
Wang resin with p-nitrophenyl chloroformate provided
the activated carbamate 2 which was reacted with
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.062
Keywords: Hydroxycinnamic acid amides; Solid-phase synthesis;
Antibacterial activity; MRSA; VRSA.
*
Corresponding author. Tel.: +662 3190931; fax: +662 3108381;
e-mail: boonek@ram1.ru.ac.th
Bioorganic & Medicinal Chemistry Letters 16 (2006) 5870–5873