Hydrophobic substituents increase the potency of salacinol, a potent α-glucosidase inhibitor from Ayurvedic traditional medicine 'Salacia'.
Using an in silico method, seven analogs bearing hydrophobic substituents (8a: Me, 8b: Et, 8c: n-Pent, 8d: n-Hept, 8e: n-Tridec, 8f: isoBu and 8g: neoPent) at the 3'-O-position in salacinol (1), a highly potent natural α-glucosidase inhibitor from Ayurvedic traditional medicine 'Salacia', were designed and synthesized. In order to verify the computational SAR assessments, their α-glucosidase inhibitory activities were evaluated in vitro. All analogs (8a-8g) exhibited an equal or considerably higher level of inhibitory activity against rat small intestinal α-glucosidases compared with the original sulfonate (1), and were as potent as or higher in potency than the clinically used anti-diabetics, voglibose, acarbose or miglitol. Their activities against human maltase exhibited good relationships to the results obtained with enzymes of rat origin. Among the designed compounds, the one with a 3'-O-neopentyl moiety (8g) was most potent, with an approximately ten fold increase in activity against human maltase compared to 1.
Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Genzoh
G
Tanabe
Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, Jiang su 210009, PR China.
Weijia
W
Xie
Department of Organic Chemistry, Telangana University, Nizamabad 503322, Telangana State, India.
Gorre
G
Balakishan
Faculty of Pharmacy, Applied Science Private University, Al Arab St 21, Amman 11931, Jordan.
Mumen F A
MF
Amer
Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Nozomi
N
Tsutsui
Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Haruka
H
Takemura
Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Shinya
S
Nakamura
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Junji
J
Akaki
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Kiyofumi
K
Ninomiya
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Toshio
T
Morikawa
Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Isao
I
Nakanishi
Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan; Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. Electronic address: muraoka@phar.kindai.ac.jp.
Osamu
O
Muraoka
D000818:Animals; D065089:Glycoside Hydrolase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D008515:Medicine, Ayurvedic; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013431:Sulfates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D065089:Glycoside Hydrolase Inhibitors; D013402:Sugar Alcohols; D013431:Sulfates; C427963:salacinol
In silico docking study; SAR study; Salacia; Salacinol; α-Glucosidase inhibitor