Synthesis of new oxadiazole derivatives as α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmc.2015.06.060

Oxadiazole derivatives (6-28) having hydrazone linkage, were synthesized through condensation reaction between benzohydrazide 5 with various benzaldehydes. The oxadiazoles derivatives (6-28) were evaluated for their α-glucosidase inhibitory activity. The IC₅₀ values for inhibition activity vary in the range between 2.64 ± 0.05 and 460.14 ± 3.25 μM. The IC₅₀ values were being compared to the standard acarbose (IC₅₀ = 856.45 ± 5.60 μM) and it was found that compounds 6-9, 12, 13, 16, 18, 20, 22-28 were found to be more active than acarbose, while other compounds showed no activity. Structure-activity relationship (SAR) studies suggest that oxadiazole benzohydrazones (6-28) inhibitory potential is dependent on substitution of the N-benzylidene part. Compound 18 (IC₅₀ = 2.64 ± 0.05 μM), which has trihydroxy substitution at C-2′, C-4′, and C-5′ on N-benzylidene moiety, recorded the highest inhibition activity that is three-hundred times more active than the standard drug, acarbose (IC₅₀ = 856.45 ± 5.60 μM). Compound 23 (IC₅₀ = 34.64 ± 0.35 μM) was found to be the most active among compounds having single hydroxyl substitution. Shifting hydroxyl from C-2′ to C-4′ (6) and C-3′ (7) reduces inhibitory activity significantly. Compounds with chlorine substituent (compounds 16, 28, and 27) showed potent activities but lower as compared to hydroxyl analogs. Substituent like nitro or methyl groups at any position suppresses enzyme inhibition activity. This reveals the important presence of hydroxyl and halo groups to have enzyme inhibitory potential.

Full text of DOI:10.1016/j.bmc.2015.06.060

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Accepted Manuscript
Synthesis of New Oxadiazole Derivatives as α-Glucosidase Inhibitors
Muhammad Taha, Nor Hadiani Ismail, Syahrul Imran, Muhammad
Qamarruddin Bin Rokei, Syed Muhammad Saad, Khalid Mohammed Khan
PII:
S0968-0896(15)00554-4
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.06.060
BMC 12416
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Accepted Date:
23 April 2015
23 June 2015
Please cite this article as: Taha, M., Hadiani Ismail, N., Imran, S., Qamarruddin Bin Rokei, M., Muhammad Saad,
S., Mohammed Khan, K., Synthesis of New Oxadiazole Derivatives as α-Glucosidase Inhibitors, Bioorganic &
Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.06.060
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Synthesis of New Oxadiazole Derivatives as α-Glucosidase Inhibitors
Muhammad Taha∗a,b, Nor Hadiani Ismaila,b, Syahrul Imrana,b, Muhammad Qamarruddin Bin Rokeib,
Syed Muhammad Saadd, and Khalid Mohammed Khand
aAtta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM),
Puncak Alam Campus, 42300, Bandar Puncak Alam, Selangor, Malaysia.
bFaculty of Applied Science Universiti Teknologi MARA (UiTM), 40450, Shah Alam, Selangor,
Malaysia cIntegrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM),
Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
dH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi-75270, Pakistan.
Abstract:
Oxadiazole derivatives (6-28) having hydrazone linkage, were synthesized through condensation
reaction between benzohydrazide 5 with various benzaldehydes. The oxadiazoles derivatives (6-28)
were evaluated for their α-glucosidase inhibitory activity. The IC50 values for inhibition activity vary
in the range between 2.64 0.05 to 460.14 3.25 µM. The IC50 values were being compared to the
standard acarbose (IC50 = 856.45 5.60 µM) and it was found that compounds 6-9, 12, 13, 16, 18, 20,
22-28 were found to be more active than acarbose, while other compounds showed no activity.
Structure-activity relationship (SAR) studies suggest that oxadiazole benzohydrazones (6-28)
inhibitory potential is dependent on substitution of the N-benzylidene part. Compound 18 (IC50 = 2.64
0.05 µM), which has trihydroxy substitution at C-2′, C-4′, and C-5′ on N-benzylidene moiety,
recorded the highest inhibition activity that is three-hundred times more active than the standard drug,
acarbose (IC50 = 856.45 5.60 µM). Compound 23 (IC50 = 34.64 0.35 µM) was found to be the
most active among compounds having single hydroxyl substitution. Shifting hydroxyl from C-2′ to C-
4′ (6) and C-3′ (7) reduces inhibitory activity significantly. Compounds with chlorine substituent
(compounds 16, 28, and 27) showed potent activities but lower as compared to hydroxyl analogs.
Substituent like nitro or methyl groups at any position suppresses enzyme inhibition activity. This
reveals the important presence of hydroxyl and halo groups to have enzyme inhibitory potential.
Keywords: Oxadiazole, benzohydrazone, antidiabetic, α-glucosidase inhibitors.
∗
Correspondence and reprints
E-mail: taha_hej@yahoo.com and muhamm9000@puncakalam.uitm.edu.my, Tel: 0060182901765

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
1. Introduction
Oxadiazole is a five membered furan type heterocyclic compound in which any two of four methines
are replaced by the nitrogen atoms. Different position of nitrogen atoms in a ring yields four possible
isomers of oxadiazole (Figure-1).
Insert figure 1 here
Among these four isomers, 1,3,4-oxadiazole is widely studied by the chemists because of its wide
applicability in research[1]. A great number of pharmacological properties have been associated with
this small but important nucleus such as anticancer [2], anti-HIV [3], antibacterial [4], anti-
inflammatory [5], anticonvulsant [6], herbicidal [7], analgesic [8], and fungicidal [9].
Oxadiazole ring has been incorporated in drug discovery programs as an essential element of
pharmacophore in contribution of ligand binding [10]. This nucleus has been revealed to function as
an aromatic linker to position substituents in the right position [11]. Raltegravir® (Figure-2) which is a
drug which contains oxadiazole as a core moiety had been used for treatment of HIV infection [12].
Two other drugs Zibotentan [13] (Figure-2) and Ataluren [14] (Figure-2), which have oxadiazole
moiety, are in the late stages of clinical trial. Oxadiazoles have been used as bioisosteric replacements
for different carbonylated compounds such as amides, carbamates, esters, and hydroxamic esters [15-
17]
Insert figure 2 here
α-Glucosidase (EC 3.2.1.20) is a glycosidic hydrolase enzyme that hydrolyzes carbohydrates into
glucose. α-Glucosidase, which is present in the brush border surface of intestinal cells, is essential in
the release of monosaccharides from carbohydrates, as human intestine only absorbs monosacharides
for blood circulation [18]. However, carbohydrate metabolism disorder results in increase of glucose
level in blood. This complication gives birth to a disease called Diabetes Mellitus (DM) [19]. Diabetes
Mellitus is managed by different classes of drugs [20,21] such as biguanides, sulfonylureas,
thiazolidinediones, and α-glucosidase inhibitors. α-Glucosidase inhibitors work by decelerating the
digestion rate in the intestine of polysaccharides into monosaccharides and thus lessen the level of
glucose in blood stream [22]. These inhibitors have been comprehensively premeditated for the
management of pre-diabetic conditions (impaired fasting glucose IFG and impaired glucose tolerance
IGT) [23,24]. α-Glucosidase inhibitors like acarbose, voglibose, and miglitol, have been designed and
instigated as drugs during last two decades [25,26]. Recently our research group has published an
article revealing the α-glucosidase inhibitory potential of oxadiazoles along with thiadiazoles [27] and
also benzohydrazide [28]. In continuation of exploring oxadiazoles as α-glucosidase inhibitors, we
2

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
have decided to synthesize a library of oxadiazole benzohydrazones (6-28) and evaluated these against
α-glucosidase in vitro. Encouraging results were found and are discussed in forthcoming paragraphs.
2. Results and Discussion
2.1 Chemistry
The synthetic route of compounds 6-28 is shown in Scheme-1 and 2. Compound 2 was synthesized by
treating methyl 2,4-dimethoxybenzoate with excess hydrazine hydrate. Compound 2 was reacted with
methyl 4-formylbenzoate in methanol with catalytic amount of acetic acid to afford hydrazone 3,
which was then subjected through an oxidative cyclization using phenyliododiacetate (PhI(OAc)2) in
dry chloroform to form oxadiazole 4. The ester functional group of compound 4 was further converted
into hydrazide by treating with hydrazine hydrate to afford compound 5.
Insert Scheme -1 here
In Scheme-2, hydrazide 5 was reacted with various benzaldehydes in the presence of acetic acid to
form the targeted oxadiazole benzohydrazone derivatives 6-28 (Table-1). The structures of the
oxadiazole benzohydrazones 6-28 were elucidated using spectroscopic techniques such as NMR, MS
and were further confirmed using CHN analysis.
Insert Scheme 2 here
2.1. Enzyme Inhibitory Studies
Studies on structure-activity relationship (SAR) proposed that α-glucosidase inhibition active of
oxadiazole benzohydrazones 6-28, is mainly reliant upon variations in substitutions on the N-
benzylidene part, attached to oxadiazole benzohydrazide.
Compound 18 (IC50 = 2.64 0.05 µM) was found to be the most active compound in the library
oxadiazole benzohydrazones 6-28, with three-hundred folds more active than the standard drug,
acarbose (IC50 = 856.45 5.60 µM). The trihydroxy substitutions at C-2′, C-4′, and C-5′, on the N-
benzylidene moiety, must have been in the best hydrogen bonding mode with the amino acid residue
of the enzyme, α-glucosidase, to inhibit it. This inhibitory trend lowered to eleven-folds when the
hydroxy was moved from C-5′ to C-6′, as in compound 13 (IC50 = 29.68 0.78 µM).
Dihydroxylation at C-3′ and C-4′, as in compound 8 (IC50 = 28.28 0.25 µM), was found to have
slightly better inhibitory activity than compound 13, that had trihydroxylation at C-2′, C-4′, and C-6′.
This reveals, how fruitful is the presence of two adjacent hydroxyl groups to interact with α-
glucosidase enzyme. Di-substitution of hydroxyl groups, para to each other, as in compound 9 (IC50 =
87.64 0.90 µM) lowered its activity up to three times w.r.t. its regio-isomer 8.
Among the monohydroxylated versions, compound having hydroxy group installed at C-2′, as in
compound 23 (IC50 = 34.64 0.35 µM), was found to be the most active. The inhibitory activity
3