Irfan Rasool1,
Matloob Ahmad1 
,
Zulfiqar Ali Khan1,
Asim Mansha1,
Tahir Maqbool1,
Ameer Fawad Zahoor1,
Sana Aslam2
For correspondence:- Matloob Ahmad Email: Matloob.Ahmad@gcuf.edu.pk Tel:+2412649975
Received: 19 August 2016 Accepted: 6 February 2017 Published: 31 March 2017
Citation: Rasool I, Ahmad M, Khan ZA, Mansha A, Maqbool T, Zahoor AF, et al. Recent advancements in oxadiazole-based anticancer agents. Trop J Pharm Res 2017; 16(3):723-733 doi: 10.4314/tjpr.v16i3.30
© 2017 The authors.
This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited..
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, 1,2,4- oxadiazole and 1,2,3-oxadiazole.
1,3,4-Oxadiazole
1,3,4-Oxadiazole derivatives are frequently reported for their anticancer activity. A series of 1-[{(5-Alkenyl/hydroxyalkenylsubstituted)-1,3,4-oxadiazol-2-yl}-methyl]-2-methyl-1H-benzimidazoles has been recently reported as anticancer agents. Among them, compounds 1, 2 & 3 showed moderate to weak activity against Hep3B (human hepatocellular carcinoma), HeLa (human cervical carcinoma) and MCF 7 (human breast adenocarcinoma) cell lines (Table 1) [1]. A series of indole and 1,3,4-oxadiazole hybrid compounds were recently prepared by Hatti and coworkers and were screened against MCF-7, KB, Colo-205, and A-549 cancer cell lines. Among them, compounds 4-8 were found to exhibit significantly higher anticancer activity as compared to the reference drug etoposide (Table 2) [2]. Rashid et al prepared 3-((5-(3-(1H-benzo[d]imidazol-2-yl)-3-oxopropyl)-1,3,4-oxadia-zol-2-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (9) which exhibited significant antiproliferative activity with GI50 value of 0.09 µM [3].
Yonova et al reported 2-phenyl-5-(phenylthio)-1,3,4-oxadiazole (10) as selective anticancer agent against the MCF-7 with EC50 value of 7.9 µM [4]. Valente et al described the synthesis of hydroxamates and 2-aminoanilides having 1,3,4-oxadiazole moiety as histone deacetylase inhibitors. Among the series of naphthalene based oxadazoles, compounds 11 and 12 appeared as the most potent and selective compounds against HDAC1. Compound 11 was more effective against U937 leukemia cells with IC50 value of 7.8 μM than reference drug (SAHA) and compound 12 displayed cell differentiation comparable to reference, MS-275 [5]. Kumar et al synthesized oxadiazole containing sulfonamides 13 and 14 which were weakly active against K562, Colo-205, MDA-MB231 and IMR-32 cancer cell lines as shown in the Table 3 [6].
Zhang et al reported the synthesis of structural hybrids of 1,3,4-oxadiazole and 1,3,4-thiadiazole heterocycles having schiff base side chain. Among these compounds, compound 15 exhibited growth inhibition of SMMC-7721 cells with IC50 value of 2.84 µM. Compounds 16 and 17 displayed antitumor activity with IC50 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 IC50 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 1,3,4-oxadiazole-2-thiol to get corresponding structural hybrids 21 and 22 which displayed excellent cytotoxic activity as shown in the [9].
1,3,4-Oxadiazoles derivatives (23 and 24) exhibited good activity with IC50 values of 16 µM and 10 µM respectively against K562 cancer cell line [10]. Shamsuzzaman et al synthesized 25 that exhibited moderate anticancer behavior against human leukemia cell line (HL-60) (IC50 =17.33) [11].
Bondock et al synthesized heterocyclic 1,3,4-oxadiazole derivatives derivatives (25-30) that displayed promising in-vitro antitumor activity as shown in the Table 6 [12]. Feng et al synthesized a series of thio-substituted 1,3,4-oxadiazole derivatives (31 & 32) and screened them against human leukemia tumor cell line (K-562). Compounds 31 and 32 were docked into the ATPase domain of TP-II and docking scores are shown in the [13].
Benzimidazole 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 IC50 values were found between 10.64 and 33.62 µM. The compounds 36, 37 & 38 exhibited anticancer activity comparable to Cisplatin () [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, 40, 41, 42 & 43 were found more active than 5-FU as shown in 0 [18]. Zhang et al synthesized 1,4-benzodioxane based 1,3,4-oxadiazoles as potential telomerase inhibitors. Compounds 44, 45, 46, 47 and 48 were observed as potent anticancer compounds with IC50 concentration range from 7.21 µM to 25.87 µM against HEPG2, SW1116, HELA and BGC823 [19].
Abu-Zaied et al synthesized novel thioglycosides having 1,3,4-oxadiazole moiety. The pharmacological evaluation of compounds 49, 50 and 51 was carried out and the compounds were found to be effective against MCF-7 (breast) and HEPG2 (liver) cells. The IC50 values were found in the range of 2.67-20.25 (µg/mL) for MCF-7 (breast cancer cell line) and 4.62-43.6 (µg/mL) for HEPG2 (liver cancer cell line) [20].
5-(3-Indolyl)-2-(substituted)-1,3,4-oxadiazoles were screened for human cancer cell lines and among the compounds, compounds 52, 53 and 54 exhibited potent cytotoxicity (IC50~1 µM) and selectivity against human cancer cell lines as shown in Table 11 [21]. Tong et al. described the synthesis of compound 55 showed the best activity with EC50 value of 3.7 µM [22]. Oxadiazole compounds 56 and 57 were appeared as potent members of anticancer family of drugs [23].
1,2,4-Oxadiazole
There are sufficient number of evidence dealing with anticancer behavious of 1,2,4-oxadiazole derivatives. 5-(5,7-Dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-3-(piperazin-1-ylmethyl)-1,2,4-oxadiazole based carboxamides, sulfonamides, ureas, and thioureas are recently reported for their effective activity against HeLa cells. Five compounds 58-62 exhibited activity with IC50 value <10 µg/cm3 which was greater than reference drug, paclitaxel with IC50 value 30 µg/cm3 [24]. Miralinaghi et al described the synthesis of triaryl-1,2,4-oxadiazole derivatives and screened them for anti-proliferative activities against MCF7 and K562 cell lines using MTT assay. Out of these, compound 63 showed remarkable activity against MCF7 and K562 cell lines with IC50 values of 6.50 and 21.66 µM, respectively [25].
Tsygankova and Zhenodarova reported a series of 3,5-Diaryl-1,2,4-oxadiazoles derivatives. Five compounds (64-68) were found more active against antitumor agents as shown in the table 12 [26]. 1,2,4-Oxadiazole (69) exhibited effective activity against DU145 (IC50 : 9.3 µM) cell lines [27].
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 IC50 value less than 5 μM as shown in the table 13 [28]. Kemnitzer et al synthesized a new series of 3-aryl-5-aryl-1,2,4-oxadiazoles. Compound 73 was found more active against T47D cancer cell growth with GI50 value of 0.13µM [29]. Kumar et al synthesized a series of 3,5-disubstituted-1,2,4-oxadiazoles. Compound 74 appeared as the most selective (>450-fold) whereas 75 as the most potent compound having IC50 value of 10 nM against prostate cancer cell lines (4) [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 5 [31].
1,2,3-Oxadiazole
In contrast to other oxadiazoles, 1,2,3-oxadiazole ring system is unstable. It isomerizes to formyldiazomethane [32, 33]. That's why, it is least studied for its biological activities.
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.
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