Recent advancements in oxadiazole-based anticancer agents

Oxadiazole ring system occupies a significant position among heterocyclic templates for medicinal compounds due to its wide spectrum of biological activities. This article entails an in-depth review of the ability of oxadiazole derivatives to induce apoptosis of cancer cells. FDA has approved a number of drugs for the treatment of different types of cancer. There is, however, a continuing need for the development of new anticancer agents due to increasing cases of drug resistance. Moreover, medicinal chemists are continuously struggling to invent selective cytotoxic agents with minimum side effects. This work reviews the significance of oxadiazole ring system and its potential to act as a template for novel anticancer agents.


INTRODUCTION
Cancer is a continued threat for humanity on the globe both in advanced countries as well as developing ones.Various anticancer drugs have been approved by FDA for the treatment of different types of cancers.Most of them are structurally based upon heterocyclic ring systems.Oxadiazole ring system is at significant position among heterocycles due its medicinal properties.This ring system exists in the form of structural isomers 1,3,4-oxadiazole, 1,2,4oxadiazole and 1,2,3-oxadiazole.
Previously, Yang et al synthesized the series of Oxadiazole derivatives as inhibitors of human leukemia HL-60 cells.Compound 70 was one of the potent anti-proliferative agent without inhibition of GST P1-1 activity.Compounds 71 and 72 exhibited antitumor activity with IC 50 value less than 5 μM as shown in the table 13 [28].Kemnitzer et al synthesized a new series of 3aryl-5-aryl-1,2,4-oxadiazoles.Compound 73 was found more active against T47D cancer cell growth with GI 50 value of 0.13µM [29].Kumar et al synthesized a series of 3,5-disubstituted-1,2,4oxadiazoles.Compound 74 appeared as the most selective (>450-fold) whereas 75 as the most potent compound having IC 50 value of 10 nM against prostate cancer cell lines (Table 14) [30].
Thiophene containing 1,2,4-oxadiazole (76) has been found as good anticancer compound against several breast and colorectal cancer cell lines as reported by Zhang et al.Moreover, compound 77 has been found to have in vivo activity in a MX-1 tumor model as shown in the Table 15 [31].

CONCLUSION
We have summed up recent literature dealing with anticancer behavior of oxadiazole ring system.Keeping in view the focus of article, we have mentioned only the potent anticancer compounds of the family.The data presented in this article is collected from recent publications in well reputed international journals of medicinal and pharmaceutical chemistry.The structural features could be interesting for medicinal chemists in devising anticancer drugs.

Table 3 :
Anti-proliferative activity (% cell survival) of compounds 13 and 14(10 µM) [9]ng these compounds, compound 15 exhibited growth inhibition of SMMC-7721 cells with IC 50 value of 2.84 µM.Compounds 16 and 17 displayed antitumor activity with IC 50 values of 4.56 and 4.25 µM, respectively against MCF-7 cells.Compounds 17 and 18 exhibited significant anti-proliferative activity against A549 cells, with IC 50 values of 4.13 and 4.11 µM, respectively [7].Quinoline substituted 1,3,4-oxadiazoles are reported for their inhibitory potential against HepG2, SGC-7901 and MCF-7 cell lines.Among the series, compounds 19 and 20 showed the best activity among the series and the results were comparable to the control as shown in table 4[8].Murty et al coupled piperazine substituted benzothiazole/benzoxazole with 1,3,4oxadiazole-2-thiol to get corresponding structural hybrids 21 and 22 which displayed excellent cytotoxic activity as shown in the Table 5[9].

Table 7 :
Docking score and IC50 values for compounds 31 and 32 [17]imidazole and oxadiazole hybrids were synthesized by Rashid et al.Amongst them, compound 33 emerged as the most significant anticancer agent against various cancer cell lines[14].Husain et al also synthesized benzimidazole and oxadiazole hybrids.Among them, compound 34 exhibited significant growth inhibition[15].Fadda et al synthesized a new series of quinoline based oxadiazoles.The compound 35 showed a strong cytotoxicity as shown in the Table 8[16].Gudipati et al synthesized a series of indole containing oxadiazoles.The compounds produced a dose dependent inhibition of the growth of HeLa cancer cell line.The IC 50 values were found between 10.64 and 33.62 µM.The compounds 36, 37 & 38 exhibited anticancer activity comparable to Cisplatin (Table9)[17].Dash et al synthesized the series of 3,5-disubstituted 1,3,4-oxa-diazole-2-thione derivatives.Among the synthesized compounds, the compounds 39

Table 10 :
Anticancer activity of oxadiazole derivatives against EAC bearing mice