Approaches for synthesis and chemical modification of non-condensed heterocyclic systems based on 1,3,4-oxadiazole ring and their biological activity: A review

Maryan Lelyukh1*, Marta Martynets2, Myroslava Kalytovska3, Iryna Drapak4, Stefan Harkov5, Taras Chaban4, Ihor Chaban1, Vasyl Matiychuk6 1Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine. 2Department of Oral Surgery and Prosthetic Dentistry FPGE, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine. 3Department of Pharmacy and Biology, Stepan Gzhytskyi National University of Veterinary Medicine and Biotechnologies Lviv, Lviv, Ukraine. 4Department of General, Bioinorganic, Physical and Colloidal Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine. 5Department of Pharmacy, Medical College of Burgas University “Prof. Dr. Asen Zlatarov”, Burgas, Bulgaria. 6Department of Organic Chemistry, Ivan Franko National University of Lviv, Lviv, Ukraine.

It is important to note that a combination of the 1,3,4-oxadiazole core with various heterocyclic fragments was accompanied by the emergence of a synergistic effect in many cases (Ahsan et al., 2011;Kotaiah et al., 2012;Padmavathi et al., 2011;Puthiyapurayil et al., 2012). Moreover, 1,3,4-oxadiazole cycle is a bioisostere for carboxylic, amide, and ester groups, which mostly contribute to the enhancement of the pharmacological activity by participating in the hydrogen bonding interactions with the receptors (Guimarães et al., 2005).
The antibacterial and antifungal activities of 5-(4-methoxy-3-fluorophenyl)isoxazole derivatives bearing 1,3,4-oxadiazole moiety were appraised against Gram-positive and Gram-negative microorganisms (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) using ampicillin as the standard and several fungi strains including Aspergillus niger, Aspergillus clavatus, and Candida albicans using griseofulvin as the standard drug. As a result, a few compounds, namely, IVa-e ( Figure 3), with promising antibacterial and antifungal action were identified (Shingare et al., 2018).
The group of 1,3,4-oxadiazole substituted 5-aryl-8hydroxy-1,6-naphthyridines was evaluated for their antiviral activity in a pseudotyped HIV cell-based assay (Johns et al., 2009a,   2009b). Among all compounds, the carboxylic acid analogs IXa and IXb (Figure 4) showed the most prominent HIV-1 integrase inhibitory activity with the ІС 50 values of 0.002 μМ. Thus, it was observed that the presence of carboxygroup in the aryl fragment is most critical for the realization of HIV-1 inhibitory action.
The antiproliferative activity of 3-arylaminomethylene substituted 5-(2-hydroxyphenyl)-1,3,4-oxadiazole-2-thiones was studied for a full 60-cell lines panel according to the National Cancer Institute (NCI, USA) methodology. The screening result data indicated that two active compounds, namely, Xa and Xb (Figure 5), exhibited a moderate cytotoxic effect and explicit selectivity against certain human cancer cell lines with a growth inhibitory values (MID GI 50 ) of −4.50 and −4.68, respectively (Aboraia et al., 2006). It was concluded that the chlorosubstituted arylamino derivatives are the most active (Xa and Xb). Furthermore, compounds with carboxylic function, namely, Xc (MID GI 50 = −4.28), Xd (MID GI 50 = −4.25), and Xe (MID GI 50 = −4.13), showed a high activity but lower than that of the chlorosubstituted analogs.

CONCLUSION
In this review, we discuss the efforts to identify new promising compounds based on aryl/heteryl substituted noncondensed 1,3,4-oxadiazole derivatives, highlighting the main approaches for obtaining a chemical modification of the mentioned heterocycles and their pharmacological profile. 1,3,4-Oxadiazole heterocycle is a very interesting and important scaffold for modern organic and medicinal chemistry which demonstrated a wide range of biological activities including anticancer, antimicrobial, antitubercular, anti-inflammatory, and analgesic action. These ring systems are also featured in various approved drug structures such as Raltegravir (antiretroviral), Zibotentan (anticancer), and Tiodazosin and Nesapidil (antihypertensive). Thereby, the variety of the synthetic approaches of substituted 1,3,4-oxadiazoles and the widespread use of them in medicinal chemistry allow establishing this template as pharmacologically significant. All of the above can be considered as a background for further in-depth studies in the areas of chemistry and pharmacology of the mentioned heterocyclic systems with possible applications in medicine.