| Abstract |
Inflammatory diseases such as asthma, atherosclerosis,
inflammatory bowel disease and cancers are major health
problems which are accountable for 38 million (68%) out of 56
million deaths reported in the world. The rising incidence of
inflammatory conditions is expected to drive the market value
of anti-inflammatory therapeutic agents to RM 446.88 billion
globally. However, currently available anti-inflammatory agents
were associated with severe adverse effects. Therefore, a
safe and effective multitarget anti-inflammatory agent is
desired. We used computational modelling approach to design
new chemical compounds which inhibit 3 target proteins
involved in the inflammatory pathways; the cyclooxygenase-2,
5-lipoxygenase and phosphodiesterase. We also ensure the
chemical compounds fulfil the Lipinski Rule of 5 and have
favorable ADME properties for oral administration. The
chemical compounds are spared from binding with COX 1 and
therefore does not have adverse effects exhibited by NSAIDs.
The multitarget anti-inflammatory lead compound was
synthesized. The inhibitory properties of the lead compound
were confirmed using specific COX2, LOX-5 and PD4
inhibition assays. We further confirmed the anti-inflammatory
effects of the lead compounds using lipopolysaccharides-
induced macrophages cell model. As far as we know, this is
the first time, novel multitarget anti-inflammatory lead
compounds were successfully designed and synthesized. |