Discovery of 2,5-Disubstituted 1,3,4-Oxadiazoles with Benzimidazole Backbone

as Potent β-Glucuronidase Inhibitors and In Silico Studies

Nik Khairunissa Nik Abdullah Zawawi1,2, Muhammad Taha1,2, Norizan Ahmat1,2,
Noraishah Abdullah1
1
Faculty of Applied Sciences, UiTM Shah Alam, 40450, Shah Alam, Selangor D. E., Malaysia.
2
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM),
Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor D. E. Malaysia.
*Corresponding author e-mail: chemtitude@yahoo.com

β-Glucuronidase (EC 3.2.1.31) is an inducible enzyme found in anaerobic Escherichia,

Bacteroides, Clostridia and Peptostreptococcus genera which catalyzes the cleavage of β-
glucuronosyl-O-bonds [1]. In human body this enzyme is present in fluids and organs such as
spleen, serum, bile, urine and kidney [2,3]. β-Glucuronidase improve activity in a diverse
pathological circumstances, such as renal diseases [4], epilepsy [5], breast, larynx, testes [6], and in
urinary tract infections [7-10]. Moreover, β-glucuronidase has been reported to be released in the
synovial fluid in the inflammatory joint diseases, for instance, rheumatoid arthritis [11,12].
Derivatives of benzimidazole are reported to be physiologically and pharmacologically active
and find application in treatment of several diseases like epilepsy, diabetes, anti-fertility etc [13,14].
Recently, several researches elucidated that biological profiles of benzimidazole analogues can
suitably be modified by the introduction of different heterocyclic moieties to exhibit a broad
spectrum of biological activities, i.e. anti-cancer and anti-fungal [15] antiviral [16], antibacterial
[17], anthelmintic [18], Anti-inflammatory [19], antihistamines [20], proton pump inhibitors [21],
antioxidant [22], antihypertensive [23], anticoagulant [24], antileukaemia [25], and anti-ulcer agents
[26]. Benzimidazoles have been applied relatively more as herbicides and in veterinary problems.
Many benzimidazoles, for examples, thiabendazole and cambendazole are used efficiently as
fungicides, herbicides and antiheliminthies. There are also some fungicides known as
2-aminoimidazolines [27]. While derivatives of 2,5-disubstituted-1,3,4-oxadiazoles reported to
show various biological activities such as anti-HIV, antifungal, antibacterial, antitubercular,
relaxants, antiinflammatory, virucidal, hypnotic, antimalarial, insecticidal, herbicidal, analgesic,
genotoxic, muscle anticonvulsant, anticancer and lipid peroxidation inhibitor [28-42].

Fig. 1. 2,5-disubstitued-1,3,4-oxadiazoles 3a-3r with benzimidazole backbone

In continuation to our efforts in developing β-glucuronidase inhibitors, novel

2,5-disubstitued-1,3,4-oxadiazoles 3a-3r with benzimidazole backbone were synthesized and
screened for their β-glucuronidase inhibitory potential (Fig.1). Synthetic compounds 3a-3r
demonstrated varying degree of β-glucuronidase inhibitory activity with IC50 values in the range of
2.14 ± 0.03 - 46.14 ± 1.26 µM, when compared to standard substrate D-saccharic acid 1,4-lactone
48.4 ± 1.25 µM. In addition, molecular docking studies were performed to explore the binding
mode of newly synthesized derivatives.

References
[1] B. Sperker, J.T. Backman, K. Kromer, Clin. Pharmacokinet. 33 (1997) 18-31.
[2] W.H. Fishman, Academic Press: New York. (1970) 519.