Abstract
Efforts to discover new drugs for Alzheimer's disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ1-42 induced neuronal cell death at 1 ?M were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ1-42 neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer's disease.
| Original language | English |
|---|---|
| Pages (from-to) | 8312-8333 |
| Number of pages | 22 |
| Journal | Molecules |
| Volume | 17 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 2012 |
| Externally published | Yes |
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Keywords
- Anti-amyloid aggregation
- Antioxidant
- BACE1 inhibitor
- Chelator
- Multifunction drugs
- Neuroprotection
ASJC Scopus subject areas
- Organic Chemistry
- Medicine(all)
Cite this
From BACE1 Inhibitor to Multifunctionality of tryptoline and tryptamine triazole derivatives for alzheimer's disease. / Jiaranaikulwanitch, Jutamas; Govitrapong, Piyarat; Fokin, Valery V.; Vajragupta, Opa.
In: Molecules, Vol. 17, No. 7, 07.2012, p. 8312-8333.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - From BACE1 Inhibitor to Multifunctionality of tryptoline and tryptamine triazole derivatives for alzheimer's disease
AU - Jiaranaikulwanitch, Jutamas
AU - Govitrapong, Piyarat
AU - Fokin, Valery V.
AU - Vajragupta, Opa
PY - 2012/7
Y1 - 2012/7
N2 - Efforts to discover new drugs for Alzheimer's disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ1-42 induced neuronal cell death at 1 ?M were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ1-42 neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer's disease.
AB - Efforts to discover new drugs for Alzheimer's disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ1-42 induced neuronal cell death at 1 ?M were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ1-42 neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer's disease.
KW - Anti-amyloid aggregation
KW - Antioxidant
KW - BACE1 inhibitor
KW - Chelator
KW - Multifunction drugs
KW - Neuroprotection
UR - http://www.scopus.com/inward/record.url?scp=84864614799&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864614799&partnerID=8YFLogxK
U2 - 10.3390/molecules17078312
DO - 10.3390/molecules17078312
M3 - Article
C2 - 22781443
AN - SCOPUS:84864614799
VL - 17
SP - 8312
EP - 8333
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 7
ER -