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    Topic review

    Novel 1,2,4-Oxadiazole Derivatives

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    Submitted by: Sebastian Demkowicz

    Definition

    Five-membered 1,2,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bioisosteric properties and an unusually wide spectrum of biological activities. Thus, it is a perfect framework for the novel drug development. After a century since the 1,2,4-oxadiazole have been discovered, the uncommon potential attracted medicinal chemists’ attention, leading to the discovery of a few presently accessible drugs containing 1,2,4-oxadiazole unit. It is worth noting that the interest in a 1,2,4-oxadiazoles’ biological application has been doubled in the last fifteen years. Herein, after a concise historical introduction, we present a comprehensive overview of the recent achievements in the synthesis of 1,2,4-oxadiazole-based compounds and the major advances in their biological applications in the period of the last five years as well as brief remarks on prospects for further development.

    1. Introduction

    Oxadiazoles are five-membered heterocyclic compounds containing one oxygen and two nitrogen atoms (historically, they were also known as furadiazoles). Depending on the position of nitrogen atoms, oxadiazoles may occur in the form of four different isomers: 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole (Figure 1). Amongst the isomers, the greatest interest is involved with 1,3,4-oxadiazoles. Their high importance is highlighted by a large number of applications in various scientific areas, e.g., pharmaceutical industry, drug discovery, scintillating materials as well as dyestuff industry [1]. It is also worth noting that compounds containing 1,3,4-oxadiazole unit exhibit a wide range of biological activities such as anticancer, antiparasitic, antifungal, antibacterial, antidepressant, anti-tubercular and anti-inflammatory [2][3][4][5].
    Figure 1. Chemical structures of oxadiazole isomers.
    According to the Web of Science data the scientific attention of 1,3,4-oxadiazoles application is continuously rising since the year 2000 (Figure 2) [6]. On the other hand, 1,2,5-oxadiazole derivatives found application mainly as High Energy Density Materials (HEDMs) as well as biologically active compounds with cytotoxic properties [7][8][9]. Due to the instability and ring-opening of 1,2,3-oxadiazole heterocycle, resulting in substituted diazomethanes formation, this isomer of oxadiazole is least of all explored [10].
    Figure 2. Number of publications containing the keywords: “1,2,4-oxadiazole” (red), “1,2,5-oxadiazole” (blue) and “1,3,4-oxadiazole” (green) in their title since 1980 [6].

    2. Historical Remarks—1,2,4-Oxadiazole

    The 1,2,4-oxadiazole heterocycle was synthesized for the very first time in 1884 by Tiemann and Krüger and was originally classified as azoxime or furo[ab1]diazole [11]. The heterocycle finally caught the attention of chemists almost 80 years after its discovery when photochemical rearrangement of it to the other heterocyclic systems was noted [12][13]. Biological activity studies of 1,2,4-oxadiazole derivatives started in the early 1940s and 20 years later First-In-Class commercial drug containing 1,2,4-oxadiazole ring—Oxolamine (Figure 3)—was described and introduced to the pharmaceutical market as a cough suppressant [14][15][16].
    Figure 3. Chemical structures of commercial drugs based on a 1,2,4-oxadiazole scaffold.
    In the last 40 years, 1,2,4-oxadiazole heterocycle has been widely explored bringing a vast number of compounds exhibiting diverse biological activities such as anticancer, anti-inflammatory, anticonvulsant, antiviral, antibacterial, antifungal, antidepressant, antiangiogenic, analgesic, anti-insomnia, anti-oedema, antiparasitic, and anti-Alzheimer. It was proved that they also show inhibitory potency against Human Deacetylase Sirtuin 2 (HDSirt2), Carbonic Anhydrase (CA), Histone Deacetylase (HDAC), Rearranged during Transfection (RET) kinase, Penicillin-Binding Protein (PBP2a), efflux pump, cyclooxygenases (COX-1 and COX-2) and butyrylcholinesterase (BChE) as well as affinity to σ1, σ2, orexin, kappa opioid (KOR) and estradiol (ER) receptors (see sections below). Furthermore, 1,2,4-oxadiazole derivatives also found application as supramolecular liquid crystals and HEDMs [7][17][18][19]. Importantly, the heterocycle demonstrates bioisosteric equivalence with ester and amide moieties due to the possibility of creation specific interaction (e.g., hydrogen bonding). It is a particularly useful alternative when the instability of those groups is observed (e.g., when the hydrolysis may appear) [20][21]. Nowadays, there are a few commercially available drugs containing 1,2,4-oxadiazole nucleus such as OxolaminePrenoxdiazine (cough suppressant, Figure 3Butalamine (vasodilator, Figure 3), Fasiplon (nonbenzodiazepine anxiolytic drug, Figure 3), Pleconaril (antiviral drug, Figure 3), Ataluren (Duchenne muscular dystrophy treatment drug, Figure 3) and Proxazole (a drug used for functional gastrointestinal disorders, Figure 3) [22][23][24]. It is worth noting that 1,2,4-oxadiazole ring, as the only one of all oxadiazole isomers, occurs in the structures of natural products. For example, in 2011 Carbone M. et al. isolated two indole alkaloids Phidianidine A and Phidianidine B (Figure 4) from sea slug Opisthobranch Phidiana militaris [25].
    Figure 4. Chemical structures of naturally occurring 1,2,4-oxadiazole-containing compounds.
    It was revealed that both Phidianidines exhibit in vitro cytotoxic activity against tumor and non-tumor mammalian cell lines (rat glial—C6, human cervical—HeLa, colon adenocarcinoma—CaCo-2, mouse embryo—3T3-L1 and rat heart myoblast—H9c2) as well as selective agonist properties against protein-tyrosine phosphatase 1B (PTP1B) and chemokine receptor type 4 (CXCR4) [26][27]Quisqualic acid (Figure 4), obtained from seeds of Quisqualis indica, is another example of naturally occurring compound bearing 1,2,4-oxadiazole. This alanine-derivative exhibits affinity to metabotropic glutamate receptor type II and IV—attractive molecular targets for the treatment of stroke, epilepsy and neurodegenerative disorders [28][29].

    3. Anticancer Agents

    Every year cancer impacts about 20 million people all over the world resulting in deaths counting in millions (Figure 5). Unfortunately, a number of new cancer cases is still rising and almost 30 million people will be diagnosed with carcinoma by 2040 in high-developed countries [30]. For that reason, finding new cancer treatments or effective drugs is one of the greatest needs of the current community and a challenge for modern medicine. Biological evaluation of 1,2,4-oxadiazoles revealed that some of their derivatives are potent anticancer agents. The greatest breakthrough came with the discovery of 3,5-diarylsubstituted derivatives of 1,2,4-oxadiazole as a new series of apoptosis inducers [31]. Since then, exploration of the anticancer activity of 1,2,4-oxadiazole derivatives has been started resulting in a creation of a wide library of compounds [32][33].
    Figure 5. Estimated number of cancer incidences and cancer-related deaths in 2018.
    Recently, Maftei C. V. et al. reported the synthesis of 4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)aniline (1Figure 6), which exhibits moderate activity with a mean IC50 value of approximately 92.4 μM against panel of 11 cancer cell lines (human colon adenocarcinoma—CXF HT-29, human gastric carcinoma—GXF 251, human lung adenocarcinoma—LXFA 629, human non-small cell lung carcinoma—LXFL 529, breast cancer-derived from athymic mice’ lung metastatic site—MAXF 401, human melanoma—MEXF 462, human ovarian adenocarcinoma—OVXF 899, human pancreatic cancer—PAXF 1657, human pleuramesothelioma cancer—PXF 1752, human renal cancer—RXF 486, human uterus carcinoma—UXF 1138). Importantly, compound 1 became a precursor for synthesis of novel compounds with greater antiproliferative activities [34].
    Figure 6. Chemical structure of 4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)aniline 1.
    Further modification of 1 led to the discovery of its derivative 2 (Table 1) exhibiting significantly greater antitumor activity evaluated against a panel of 12 human tumor cell lines (CXF HT-29, GXF 251, LXFA 629, LXFL 529, MAXF 401, MEXF 462, OVXF 899, PAXF 1657, human prostate cancer—PRXF 22Rv1, PXF 1752, RXF 486 and UXF 1138), especially toward OVXF 899 and PXF 1752 cell lines with the IC50 values of 2.76 and 9.27 μM, respectively. Moreover, compound 2 showed high selectivity against renal cancer cell line with the IC50 = 1.143 μM [35]. In addition, the same research team reported new gold(I) complexes with 1,2,4-oxadiazole-containing N-heterocyclic carbene ligands. Obtained results clearly revealed impressive potency of imidazolium salts. The most active derivative 3 (Table 1) showed extremely low IC50 values from 0.003 to 0.595 μM against the same panel of 12 cancer cell lines with highest activity in an in vitro assays with LXFA 629 and MAXF 401 cells (IC50 = 0.003 μM for both of them) [36]. Thus, 3 seems to be an ideal candidate for further evaluation. More advanced in vivo studies may reveal some additional features, although no information has been published up to date.
    Table 1. 1,2,4-oxadiazole derivatives with antitumor activity.
    General Structure Substituents The Most Active Derivatives Activity Ref.
    Pharmaceuticals 13 00111 i022 R1 = H, NH2 and other (see Ref.);
    R2 = H or phenyl.
    Pharmaceuticals 13 00111 i023 IC50 values of 2.76 and 9.27 μM against OVXF 899 and PXF 1752 cancer cell lines, respectively. [35]
    Pharmaceuticals 13 00111 i024 X = Cl or Br;
    R1 = methyl, benzyl, 2-pyridinyl or anthracen-9-ylmethyl.
    Pharmaceuticals 13 00111 i025 IC50 values of 3 nM against LXFA 629 and MAXF 401 cancer cell lines, respectively. [36]
    Pharmaceuticals 13 00111 i026 X = O or NH;
    R1 = phenyl, benzyl, 2-chlorophenyl, 4-fluorophenyl, 2-mehylphenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-pyridinyl, 2-methoxyphenyl, 2-benzyloxyphenyl or 3-pyridinyl.
    Pharmaceuticals 13 00111 i027 IC50 values between 26.1–34.3 μM against Colo 205, Hep G2 and Hela cell lines. [37][38]
    Pharmaceuticals 13 00111 i028 R1 = methyl, chloromethyl or phenyl. Pharmaceuticals 13 00111 i029 GI50 values of 0.08 (5a) and 0.34 (5bμM against CEM-13 cell line. [39]
    Pharmaceuticals 13 00111 i030 R1 = H, Br, Cl, F, methoxy or NH2. Pharmaceuticals 13 00111 i031 CC50 values of 137.3, 79.0 and 140.3 μM against Ca9-22 cell line, respectively. [40]
    Pharmaceuticals 13 00111 i032 R1 = H, 2-chloro, 3-chloro, 4-chloro, 4-nitro, 4-methyl, 4-methoxy, 4-trifluoromethyl, 2-bromo, 3-bromo, 4-bromo or 4-fluoro;
    R2 = N(CH3)2, N(C2H5)2, pyrrolidine-1-yl, azepan-1-yl, morpholin-1-yl, thiomorpholine-1-yl, N-methylpiperazin-1-yl, N-phenylpiperazin-1-yl, 3-bromopropan-1-yl or 3-chloropropan-1-yl.
    Pharmaceuticals 13 00111 i033 80% of death of NB4, K562 and MDA-MB-231 cancer cell lines at 25 (7a) and 10 (7bμM. [41]
    Pharmaceuticals 13 00111 i034 R1 = H or NH2;
    R2 = isopropylidene or cyclopentylidene;
    R3 = 4-nitrophenyl, 4-chlorophenyl or 3,4,5-trimethylphenyl.
    Pharmaceuticals 13 00111 i035 GI50 of 4.5 μM against WiDr cancer cell line. [42]
    Pharmaceuticals 13 00111 i036 R1 = CH3 or —(CH2)4—;
    R2 = H, Cl, Br, methyl or methoxy.
    Pharmaceuticals 13 00111 i037 IC50 values of 0.48 (9a), 0.78 (9b), 0.19 (9cμM against MCF-7 cancer cell line. [43]
    Pharmaceuticals 13 00111 i038 R1 = H, 3-methyl, 4-methyl, 3-bromo, 4-methoxy, 4-trifluoromethyl, 4-chloro, 4-bromo or 4-fluoro. Pharmaceuticals 13 00111 i039 IC50 values between 13.6–48.37 μM against HCT-116, PC-3, SNB-19, B16F10, L929 cell lines. [44]
    Pharmaceuticals 13 00111 i040 R1 = H, 3,4,5-trimethoxy, 4-methoxy, 4-chloro, 4-bromo, 4-fluoro, 4-trifluoromethyl, 4-nitro, 4-cyano or 4-methyl. Pharmaceuticals 13 00111 i041 IC50 values in a range from 0.11 to 2.09 μM against MCF-7, A375 and HT-29 cancer cell lines. [45]
    Pharmaceuticals 13 00111 i042 R1 = H, 3,4,5-trimethoxy, 4-methoxy, 4-chloro, 4-bromo, 4-fluoro, 4-trifluoromethyl, 4-nitro, 4-cyano or 4-methyl. Pharmaceuticals 13 00111 i043 IC50 values between 0.011–1.89 μM against A549, MCF-7, A375 and HT-29 cancer cell lines. [46]
    Pharmaceuticals 13 00111 i044 R1 = H, 3,4,5-trimethoxy, 4-methoxy, 4-chloro, 4-bromo, 4-fluoro, 4-trifluoromethyl, 4-nitro, 3-nitro or 4-methyl. Pharmaceuticals 13 00111 i045 IC50 values in a range of 0.11–1.47 μM against A375, MCF-7 and ACHN cancer cell lines. [47]
    Pharmaceuticals 13 00111 i046 R1 = H, 3,4,5-trimethoxy, 4-methoxy, 4-chloro, 4-bromo, 4-fluoro, 4-trifluoromethyl, 4-nitro, 4-cyano or 4-methyl. Pharmaceuticals 13 00111 i047 IC50 values between 0.12–2.78 μM against MCF-7, A549 and A375 cancer cell lines. [48]
    Pharmaceuticals 13 00111 i048 R1 = methyl, phenyl, 4-fluorophenyl, benzyl or 4-methoxbenzyl;
    R2 = phenyl, 9-phenanthryl or 4-pyridinyl;
    R3 = 4-nitrophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl or 4-fluorophenyl.
    Pharmaceuticals 13 00111 i049 IC50 value of 10.38 μM toward MCF-7 cancer cell line. [49]
    Pharmaceuticals 13 00111 i050 R1 = methyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-t-butylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, cyclopropyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-thienyl, 3-thienyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl or 3,4-dichlorophenyl;
    Ar1 = p-phenylene, m-phenylene, p-methoxyphenylene or 2,4-thienyl.
    Pharmaceuticals 13 00111 i051 Ki value of 89 pm and 0.75 nm (hCA IX and hCA II, respectively) for 16a in CO2 hydration stopped-flow biochemical assay.
    16b showed high selectivity toward PANC-1 cancer cell line.
    [50][51]
    Pharmaceuticals 13 00111 i052 R1 = H, F, Cl, Br or methoxy;
    R2 = H, F or Br.
    Pharmaceuticals 13 00111 i053 IC50 values of 0.65 (17a) and 2.41 μM (17b) against MCF-7 cancer cell line. [52]
    Pharmaceuticals 13 00111 i054 R1 = H, 3,4,5-trimethoxy, 4-methoxy, 4-chloro, 4-bromo, 4-fluoro, 4-nitro, 3-nitro, 4-cyano or 4-trifluoromethyl. Pharmaceuticals 13 00111 i055 IC50 values in a range of 0.45–2.11 μM against MCF-7, A549, MDA-MB-231 cancer cell lines. [53]
    Pharmaceuticals 13 00111 i056 XY = N, O or O, N;
    n = 5 or 6;
    R1 = H, 2-methyl, 4-methyl, 4-methoxy, 2-fluoro, 3-fluoro, 4-fluoro, 4-bromo or 4-nitro.
    Pharmaceuticals 13 00111 i057 IC50 values of 8.2, 10.5, 12.1 nM (20a20b20c, respectively) toward HDAC-1. [54][55]
    Pharmaceuticals 13 00111 i058 R1 = H, 4-methyl, 3-methyl, 2-fluoro, 4-fluoro, 2,4-difluoro, 2-chloro, 4-cyano, 4-trifluoromethyl or 2-chloro-4-fluoro. Pharmaceuticals 13 00111 i059 IC50 values of 1.8, 3.6 and 3.0 nM against HDAC-1, -2 and -3, respectively. [56]
    Pharmaceuticals 13 00111 i060 R1 = 3-pyridinyl, 4-pyridinyl, 4-methoxy-3-pyridinyl, 5-(2-methoxyethoxy)-3-pyridinyl, 5-morpholin-3-pyridinyl or 5-(1-methyl-1H-pyrazol-3-yl)-3-pyridinyl. Pharmaceuticals 13 00111 i061 IC50 value of 7.3 nM against RET enzyme in ELISA assay. [57]
    In a study reported by Challa K., Krishna C. and coworkers C28-modified Betulinic Acid (Figure 7) bearing 1,2,4-oxadiazole ring connected via ester or amide linker have been synthesized and evaluated against human colon carcinoma (Colo 205), human liver cancer (Hep G2) and HeLa cell lines [37][38]. Performed screening revealed moderate potential of all obtained derivatives with the highest biological activities for analogs 4a–4d (Table 1) (the IC50 values in a range of 26.1–34.3 μM). However, the obtained compounds turned out to be still weaker than reference compound—etoposide (the IC50 values of 0.42–22.5 μM), a topoisomerase II enzyme inhibitor, which is currently used as medication in the treatment of cancer diseases (e.g., lung, ovarian, testicular cancers, leukemia, neuroblastoma and lymphoma) [58]. Interestingly, the impact on the biological activity of compounds by switching the ester moiety with amide was negligible.
    Figure 7. Chemical structure of Betulinic Acid and Lambertianic Acid.
    Mironov et al. carried out a synthesis of several derivatives of Lambertianic acid (Figure 7) by the introduction of substituted-1,2,4-oxadiazole heterocycle at the C16 position [39]. Obtained compounds were tested in comparison with doxorubicin—widely used anticancer agent in the treatment of breast, bladder carcinomas, lymphoma, and acute lymphocytic leukemia [59][60]. Obtained outcomes by Mironov et al. revealed that 5ab (Table 1) exhibited more favorable biological activity than Lambertianic Acid itself with the GI50 values at sub-micromolar concentration against human childhood and adult T acute lymphoblastic leukemia (CEM-13), MT-4, and human adult acute monocytic leukemia (U-937) cancer cell lines. It is worth noting that 5ab demonstrated greater cytotoxic activity than doxorubicin. Additional biological studies indicated that activities of 5ab against human breast adenocarcinoma—MCF-7, MDA-MB-231 and human melanoma—MEL-8 cancer cell lines were slightly lower than the reference compound. Interestingly, flow cytometry assay revealed that the above-mentioned compounds are potent inducers of apoptosis in MCF-7, MDA-MB-231 and MEL-8 cell lines and are acting in a dose-dependent manner.
    In the study of Kucukoglu K. et al. a series of Schiff bases fused with 1,2,4-oxadiazole heterocycle has been synthesized and evaluated in vitro against a panel of 8 cancer cell lines [40]. Results revealed that 6ac (Table 1) exhibited higher biological potency (CC50 = 137.3, 79.0 and 140.3 μM, respectively) against Ca9-22 cell line than 5-fluorouracil (a multi-acting agent used in the treatment of colon, esophageal, stomach, breast and pancreatic cancers) applied as a reference (CC50 = 214.3 μM). On the other hand, the cytotoxic potency of obtained compounds occurred to be far weaker than doxorubicin. For this reason, modifications of chemical structure including a different substitution of terminal aromatic rings or an introduction of additional pharmacophores are worth of consideration to improve biological activity.
    Moniot S., Forgione M. et al. reported a study of about 40 novel substituted 3-aryl-5-alkyl-1,2,4-oxadiazole derivatives as selective inhibitors of HDSirt2—NAD+ lysine deacetylase—an attractive target for treating neurodegenerative disorders, metabolic dysfunctions, age-related diseases and cancer [41]. The biological activity of obtained derivatives was assessed in a continuous assay using an α-tubulin-acetylLys40 peptide as a substrate. Based on the detailed structure-activity relationship (SAR) studies, compounds 7a and 7b (Table 1) emerged as the most potent HDSirt2 inhibitors when tested against human leukemia cell lines (U-937, NB4, HL-60, and K562) and MDA-MB-231 cell line. Analog 7a was able to induce apoptotic death in over 80% of NB4, K562 and MDA-MB-231 cancer cell at the concentration of 25 μM. Moreover, 7b achieved the same effect at 10 μM. According to the western blot analyses, the involvement of HDSirt2 inhibition for apoptotic death induction has been confirmed. In addition, the crystal structure of 1,2,4-oxadiazole derivatives in complex with HDSirt2 revealed yet unexplored subcavity, which may be extremely useful for further inhibitors development [41].
    In 2017, Avanzo R. E. and coworkers synthesized 9 novel diheterocyclic-ribose fused derivatives containing 5-substituted-1,2,4-oxadiazole framework. Their previous study suggested that 5-deoxy-5-S-(1,2,4-triazol-3-yl)-2,3-O-cyclopentylidene-β-D-ribofuranoside derivatives are moderate antitumor agents. It turned out that the introduction of 5-substituted-1,2,4-oxadiazole heterocycle into the ribose-derivative structure improved anticancer activity [42][61]. Obtained compounds were tested against human lung (A549), SW1573, HeLa, human breast (HBL-100), T-47D, and human colon (WiDr) cancer cell lines. Among them, compound 8 (Table 1) showed the highest antiproliferative potency and selectivity against WiDr with the GI50 value of 4.5 μM. It was noticed that the presence of electron withdrawing group (EWG) at the para position of the aromatic ring occurred to be crucial to ensure high biological activity.
    Recently, Abd el hameid M. K. reported 15 novel 1,2,4-oxadiazole derivatives as analogs of TerthiopeneTerpyridine, and Prodigiosin (Figure 8)—naturally occurring compounds with potent cytotoxic and pro-apoptotic properties against various types of carcinoma [43]. Obtained compounds were preliminary evaluated against MCF-7 cancer cell line and the most potent were selected for further evaluation toward human colon cancer—HCT-116 cell line. Obtained results revealed that 9ac (Table 1) exhibited the highest activity with the IC50 values of 0.48, 0.78, 0.19 μM and 5.13, 1.54, 1.17 μM against MCF-7 and HCT-116, respectively. In addition, their biological activities were comparable or greater than reference Prodigiosin (the IC50 values of 1.93 and 2.84 μM against MCF-7 and HCT-116 cell line, respectively). Interestingly, flow cytometry analysis revealed that the above-mentioned compounds were able to arrest cell proliferation at G1 phase in MCF-7 cells and were triggering apoptosis via increasing of caspase3/7 activity, thus are suitable for further development as potent anticancer agents.
    Figure 8. Chemical structure of TerthiopeneTerpyridine, and Prodigiosin.

    4. Antimicrobial Agents

    So far literature have listed over 1400 different species of microbials (including bacteria, viruses, protozoa, fungi and helminthes) able to elicit illnesses in human body which very often leads to death. Surprisingly, only 20 of them (mainly bacteria) are responsible for approximately two thirds of the fatal cases [62]. Estimated deaths from infections is continuously falling, from 16 million in 1990 to approximately 15 million to forecasting 13 million in 2050 in high-developed countries. However, people are still suffering an enormous burden dint of pneumonia, HIV/AIDS, tuberculosis, malaria, diarrhea and many other diseases [63][64]. In light of the numerous pandemic threats in European countries and the world, including the recent infections with the SARS-CoV-2 virus causing COVID-19, discovering new, effective antibacterial/antiviral drugs and the development of modern therapies are two challenges of paramount importance.
    In 2014 O’Daniel P. I., Mobashery S., and Chang M. et al. from the University of Notre Dame in the United States put a great effort into the development of 1,2,4-oxadiazole as new antibiotics and discovered a new class of non-β-lactam drugs that were able to inhibit PBP2a of Methicillin-Resistant Staphylococcus aureus (MRSA) [65]. Detailed computer screening allowed to select 29 compounds from 1.2 million compounds (ZINC database), which were tested for their antibacterial activity against ESKAPE pathogens and agent 23 (Table 2) emerged as the most promising. Its further evaluation brought an enormous number of derivatives and led to the discovery of 24 (Table 2), which exhibited superior antibacterial activity against Vancomycin-Resistant Saureus (VRSA), Vancomycin-Resistant Enterococcus faecium (VRE) as well as MRSA with the MIC values ranging from 1 to 2 μg/mL. Moreover, rapid-time kill kinetics studies revealed that 24 was able to cause instant cell death of VRE and Daptomycin-non-Susceptible isolates at 4 mg/L in 1 h resulting in better outcomes than reference compound—daptomycin [66]. Further modifications of 24 and very detailed SAR analysis allowed to obtain a wide library of its analogs (counting in hundreds of derivatives) and resulting in discovery of 5-(1H-indol-5-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole (also called as ND-421Table 2). ND-421 exhibited longer half-time, a high volume of distribution, low clearance, excellent bioavailability, 3 times longer postantibiotic effect than linezolid without inoculum effect with unaltered biological activity [67][68][69]. Additionally, in vitro studies against Saureus, which exhibits two- and four-fold increased resistance, revealed first-time-reported, unique resistance mechanism to 1,2,4-oxadiazoles in MRSA. Moreover, those pathogen mutants did not show increased resistance to ampicillin, imipenem, linezolid, and vancomycin antibiotics (which are last drug-based defense against MRSA and VRSA) which made ND-421 a perfect alternative drug for refractory microorganisms [70]. It is also worth pointing out that ND-421 showed high synergy with other β-lactams (oxacillin, piperacillin, imipenem, meropenem and cefepime) unlike to non-β-lactam antibiotics (vancomycin, linezolid, gentamicin, doxycycline and azithromycin). Recently, the same research team performed additional in vitro studies of ND-421 against 210 different MRSA and VRE, which exhibited the MIC50 values of 4 μg/mL in all examined strains. Moreover value of MIC50 were consistently lowered when studied compound was used in combination with oxacillin [71][72]. In summary, 1,2,4-oxadiazoles 2324 and ND-421 are extremely potent and very promising non-β-lactam bactericidal antibiotics against Gram-positive multi-resistant bacteria suitable for further in vivo evaluation and clinical studies, although no information has been published up to date.
    Table 2. 1,2,4-oxadiazole derivatives and their antimicrobial activity.
    General Structure Substituents The Most Active Derivatives Activity Ref.
    Pharmaceuticals 13 00111 i062 R1 = H, OH, OCH3, NH2, NHAc, NH3Cl, NHMs, NH-nBu, NH-tBu, NHCOPh, NH-iPr, PO3H2, PO(OEt)2, SO2NH2, CONH2, COOH, COOCH3 F, Cl, Br, I, NO2, ethynyl or CN;
    Ar1 = phenyl, benzyl, 2-pyrole, 3-pyridyl, 4-pyridyl, 5-indole, 3-pyrrazole, 2-imidazole and many others (see Ref.);
    Ar2Ar3 = p-phenylene, 6-indole, 2-pyridyl, 6-chromene, carbazole, N-phenylpiperazine, N-phenylmorpholine and many others (see Ref.);
    X = NH, CH2, O, CO, NBn, SO or SO2.
    Pharmaceuticals 13 00111 i063 MIC50 values <4 μg/mL against over 210 diverse, MRSA and VRE strains. [65][67][68][72]
    Pharmaceuticals 13 00111 i064 X = NH or none;
    R1 = H, 3-chloro-4-fluorophenyl, 2-chlorophenyl, 2-ethyl, 4-ethyl, 5-bromo-2-fluorophenyl or 2-methylpyridin-5-yl.
    Pharmaceuticals 13 00111 i065 Grown inhibition zone within 20–25 mm against SaureusBsubtilisEcoliPvulgarisPaeruginosaCalbicans. [73]
    Pharmaceuticals 13 00111 i066 R1 = H, 2-chloro or 3-chloro;
    X = CH or N;
    R2 = H, 2-nitro, 2-chloro, 3-bromo, 2-chloro-5-nitro, 2-bromo, 3-nitro, 2-iodo, 3,5-dinitro, 4-nitro or 2-hydroxy.
    Pharmaceuticals 13 00111 i067 MIC value of 60 μM against Ecoli. [74]
    Pharmaceuticals 13 00111 i068 R1 = H, F, Cl, Br, I, methyl, ethyl, methoxy or iPr;
    R2 = H, methyl, methoxy, iPr, F, Cl, Br or I;
    R3 = H, F, Cl, Br, nitro, iPr, OBn, methoxy, ethoxy or CN.
    Pharmaceuticals 13 00111 i069 MIC value of 64 μg/mL against Sepidermidis. [75]
    Pharmaceuticals 13 00111 i070 R1 = H or methyl;
    Ar1 = p-phenylene or m-phenylene;
    R2 = methyl, cyclopropyl, 2-thienyl, 2-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 4-ethylphenyl, 4-t-butylphenyl, 4-methylphenyl, 3,4,-dimethylphenyl and many others (see Ref.).
    Pharmaceuticals 13 00111 i071 MIC values in a range 8–16 μg/mL toward SaureusBsubtilisEcoliPfluorescent. [76]
    Pharmaceuticals 13 00111 i072 R1 = phenyl, 4-mehtoxyphenyl, 4-chlorophenyl, 3-methylthienyl or 2-pyridinyl;
    R2R3 = H, methyl, phenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4,-dimethoxyphenyl or 2,3-dimethoxyphenyl.
    Pharmaceuticals 13 00111 i073 MIC value of 0.68 mM against Saureus. [77]
    Pharmaceuticals 13 00111 i074 R1 = phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-3-dichlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-hydroksyphenyl, 2-bromo-4-fluorophenyl, 4-cyanophenyl, 4-pyridinyl, 1-napthyl and others (see Ref.). Pharmaceuticals 13 00111 i075 IC50 value of 0.045 μg/mL against Mtuberculosis (H37Ra). [78]
    Pharmaceuticals 13 00111 i076 R1 = 4-pyridyl, 3-pyridinyl or 3,5-difluorophenyl;
    R2 = 3,5-dimethoxyphenyl, 3,5-difluorophenyl, 3-cyanophenyl, 2,3-dimethylphenyl, cyclopentyl or 4-izopropylphenyl.
    Pharmaceuticals 13 00111 i077 MIC value of 0.5 μg/mL against Mtuberculosis (H37Ra). [79]
    Pharmaceuticals 13 00111 i078 R1 = H, F, Cl, Br, methyl, nitro, methoxy or hydroxy;
    R2 = 4-hydroksy-3-methoxyphenyl, 2-styryl, ferrocene or 5-benzo[1,3]dioxole.
    Pharmaceuticals 13 00111 i079 IC50 value of 0.02 μM against Pfalciparum.
    In vivo studies failed—none in vivo activity.
    [80]
    Pharmaceuticals 13 00111 i080 R1 = Me, Et, cyclopropyl, iPr, CF3iBu or CH2OCH3;
    Ar1 = p-phenylene, p-2-methylphenylene, p-2,6-dimethylphenylene, 2,5-pyridinyl or 3-methylbenzothiophene
    Pharmaceuticals 13 00111 i081 IC50 values of 66.0, 22.0 and 3.7 nM against hRV-B14, hRV-A21 and hRV-A71, respectively. [81]

    The entry is from 10.3390/ph13060111

    References

    1. Salahuddin; Mazumder, A.; Yar, M.S.; Mazumder, R.; Chakraborthy, G.S.; Ahsan, M.J.; Rahman, M.U. Updates on synthesis and biological activities of 1,3,4-oxadiazole: A review. Synth. Commun. 2017, 47, 1805–1847.
    2. Bajaj, S.; Asati, V.; Singh, J.; Roy, P.P. 1,3,4-Oxadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents. Eur. J. Med. Chem. 2015, 97, 124–141.
    3. Bala, S.; Saini, V.; Kamboj, S.; Prasad, D.N. Review Exploring Antiinflammatory Potential of 1,3,4-Oxadiazole Derivatives as Promising Lead. Int. J. Pharm. Sci. Rev. Res. 2012, 17, 84–89.
    4. Khalilullah, H.J.; Ahsan, M.; Hedaitullah, M.; Khan, S.; Ahmed, B. 1,3,4-Oxadiazole: A Biologically Active Scaffold. Mini-Rev. Med. Chem. 2012, 12, 789–801.
    5. Bajaj, S.; Roy, P.P.; Singh, J. 1,3,4-Oxadiazoles as Telomerase Inhibitor: Potential Anticancer Agents. Anti-Cancer Agents Med. Chem. 2018, 17, 1869–1883.
    6. WebOfScience. Available online: (accessed on 16 December 2019).
    7. Wei, H.; He, C.; Zhang, J.; Shreeve, J.M. Combination of 1,2,4-Oxadiazole and 1,2,5-Oxadiazole Moieties for the Generation of High-Performance Energetic Materials. Angew. Chem. 2015, 127, 9499–9503.
    8. Boiani, M. 1,2,5-Oxadiazole N-oxide derivatives as potential anti-cancer agents: Synthesis and biological evaluation. Part IV. Eur. J. Med. Chem. 2001, 36, 771–782.
    9. Fershtat, L.L.; Makhova, N.N. 1,2,5-Oxadiazole-Based High-Energy-Density Materials: Synthesis and Performance. ChemPlusChem 2020, 85, 13–42.
    10. Nguyen, M.T.; Hegarty, A.F.; Elguero, J. Can 1,2,3-Oxadiazole be Stable? Angew. Chem. Int. Ed. Engl. 1985, 24, 713–715.
    11. Tiemann, F.; Krüger, P. Ueber Amidoxime und Azoxime. Berichte Der Dtsch. Chem. Ges. 1884, 17, 1685–1698.
    12. Newman, H. Photochemistry of 3,5-diphenyl-1,2,4-oxadiazole II. Photolysis in protic media. Tetrahedron Lett. 1968, 9, 2421–2424.
    13. Newman, H. Photochemistry of 3,5-diphenyl-1,2,4-oxadiazole I. Photolysis in aprotic media. Tetrahedron Lett. 1968, 9, 2417–2420.
    14. Anderson, G.W.; Faith, H.E.; Marson, H.W.; Winnek, P.S.; Roblin, R.O. Studies in Chemotherapy. VI. Sulfanilamido Heterocycles. J. Am. Chem. Soc. 1942, 64, 2902–2905.
    15. Silvestrini, B.; Catanese, B. Ricerche sul metabolismo del 5-beta-dietilamino-3-alfa -fenilpropil-1,2,4-oxadiazolo. Bollettino Chimico Farmaceutico 1964, 103, 447–450.
    16. Silvestrini, B. Un antitosse-antinfiammatorio, l’Oxolamina (Perebron). Minerva Medica 1960, 51, 4091–4094.
    17. Parra, M.; Hidalgo, P.; Alderete, J. New supramolecular liquid crystals induced by hydrogen bonding between pyridyl-1,2,4-oxadiazole derivatives and 2,5-thiophene dicarboxylic acid. Liq. Cryst. 2005, 32, 449–455.
    18. Xiong, H.; Yang, H.; Lei, C.; Yang, P.; Hu, W.; Cheng, G. Combinations of furoxan and 1,2,4-oxadiazole for the generation of high performance energetic materials. Dalton Trans. 2019, 48, 14705–14711.
    19. Yan, T.; Cheng, G.; Yang, H. 1,2,4-Oxadiazole-Bridged Polynitropyrazole Energetic Materials with Enhanced Thermal Stability and Low Sensitivity. ChemPlusChem 2019, 84, 1567–1577.
    20. Pitasse-Santos, P.; Sueth-Santiago, V.; Lima, M. 1,2,4- and 1,3,4-Oxadiazoles as Scaffolds in the Development of Antiparasitic Agents. J. Braz. Chem. Soc. 2017, 29, 435–456.
    21. Rosa, M.F.; Morcelli, A.C.T.; Lobo, V.S. 1,2,4-Oxadiazole: A Brief Review From The Literature About the Synthesis and Pharmacological Applications. Vis ao Acadêmica Curitiba 2015, 16, 130–157.
    22. Coupar, I.M.; Hedges, A.; Metcalfe, H.L.; Turner, P. Effect of aminophylline, butalamine and imolamine on human isolated smooth muscle. J. Pharm. Pharmacol. 1969, 21, 474–475.
    23. Rotbart, H.A.; Webster, A.D. Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril. Clin. Infect. Dis. 2001, 32, 228–235.
    24. McDonald, C.M.; Campbell, C.; Torricelli, R.E.; Finkel, R.S.; Flanigan, K.M.; Goemans, N.; Heydemann, P.; Kaminska, A.; Kirschner, J.; Muntoni, F.; et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017, 390, 1489–1498.
    25. Carbone, M.; Li, Y.; Irace, C.; Mollo, E.; Castelluccio, F.; Di Pascale, A.; Cimino, G.; Santamaria, R.; Guo, Y.W.; Gavagnin, M. Structure and Cytotoxicity of Phidianidines A and B: First Finding of 1,2,4-Oxadiazole System in a Marine Natural Product. Org. Lett. 2011, 13, 2516–2519.
    26. Vitale, R.M.; Gatti, M.; Carbone, M.; Barbieri, F.; Felicità, V.; Gavagnin, M.; Florio, T.; Amodeo, P. A minimalist hybrid ligand/receptor-based pharmacophore model for CXCR4 applied to a small-library of marine natural products led to the identification of Phidianidine A as a new CXCR4 ligand exhibiting antagonist activity. ACS Chem. Biol. 2013, 8, 2762–2770.
    27. Zhang, L.; Jiang, C.S.; Gao, L.X.; Gong, J.X.; Wang, Z.H.; Li, J.Y.; Li, J.; Li, X.W.; Guo, Y.W. Design, synthesis and in vitro activity of phidianidine B derivatives as novel PTP1B inhibitors with specific selectivity. Bioorg. Med. Chem. Lett. 2016, 26, 778–781.
    28. Hermit, M.B.; Greenwood, J.R.; Bräuner-Osborne, H. Mutation-induced Quisqualic Acid and Ibotenic Acid Affinity at the Metabotropic Glutamate Receptor Subtype 4. J. Biol. Chem. 2004, 279, 34811–34817.
    29. Kozikowski, A.P.; Steensma, D.; Varasi, M.; Pshenichkin, S.; Surina, E.; Wroblewski, J.T. α-substituted quisqualic acid analogs: New metabotropic glutamate receptor group II selective antagonists. Bioorg. Med. Chem. Lett. 1998, 8, 447–452.
    30. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424.
    31. Zhang, H.Z.; Kasibhatla, S.; Kuemmerle, J.; Kemnitzer, W.; Ollis-Mason, K.; Qiu, L.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S.X. Discovery and Structure-Activity Relationship of 3-Aryl-5-aryl-1,2,4-oxadiazoles as a New Series of Apoptosis Inducers and Potential Anticancer Agents. J. Med. Chem. 2005, 48, 5215–5223.
    32. Pace, A.; Buscemi, S.; Piccionello, A.P.; Pibiri, I. Recent Advances in the Chemistry of 1,2,4-Oxadiazoles. In Advances in Heterocyclic Chemistry; Academic Press Inc.: Cambridge, MA, USA, 2015; Volume 116, pp. 85–136.
    33. Rasool, I.; Ahmad, M.; Khan, Z.A.; Mansha, A.; Maqbool, T.; Zahoor, A.F.; Aslam, S. Recent advancements in oxadiazole-based anticancer agents. Trop. J. Pharm. Res. 2017, 16, 723.
    34. Maftei, C.V.; Fodor, E.; Jones, P.G.; Franz, M.H.; Kelter, G.; Fiebig, H.; Neda, I. Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties. Beilstein J. Org. Chem. 2013, 9, 2202–2215.
    35. Maftei, C.V.; Fodor, E.; Jones, P.G.; Daniliuc, C.G.; Franz, M.H.; Kelter, G.; Fiebig, H.H.; Tamm, M.; Neda, I. Novel 1,2,4-oxadiazoles and trifluoromethylpyridines related to natural products: Synthesis, structural analysis and investigation of their antitumor activity. Tetrahedron 2016, 72, 1185–1199.
    36. Maftei, C.V.; Fodor, E.; Jones, P.G.; Freytag, M.; Franz, M.H.; Kelter, G.; Fiebig, H.H.; Tamm, M.; Neda, I. N -heterocyclic carbenes (NHC) with 1,2,4-oxadiazole-substituents related to natural products: Synthesis, structure and potential antitumor activity of some corresponding gold(I) and silver(I) complexes. Eur. J. Med. Chem. 2015, 101, 431–441.
    37. Krishna, C.; Bhargavi, M.V.; Krupadanam, G.L.D. Design, Synthesis, and Cytotoxicity of Semisynthetic Betulinic Acid-1,2,4-Oxadiazole Amide Derivatives. Russ. J. Gen. Chem. 2018, 88, 312–318.
    38. Challa, K.; Bhargavi, M.V.; Krupadanam, G.L.D. Design, semisynthesis and cytotoxic activity of novel ester derivatives of betulinic acid-1,2,4 oxadiazoles. J. Asian Nat. Prod. Res. 2016, 18, 1158–1168.
    39. Mironov, M.E.; Pokrovsky, M.A.; Kharitonov, Y.V.; Shakirov, M.M.; Pokrovsky, A.G.; Shults, E.E. Furanolabdanoid-based 1,2,4-oxadiazoles: Synthesis and cytotoxic activity. ChemistrySelect 2016, 1, 417–424.
    40. Kucukoglu, K.; Tugrak, M.; Demirtas, A.; Sakagami, H.; Gul, H.I. Synthesis and Cytotoxic Activity of (4-Substituted-benzylidene)-(3-Phenyl-1,2,4-Oxadiazol-5-YL)Methylamines. Pharm. Chem. J. 2016, 50, 234–238.
    41. Moniot, S.; Forgione, M.; Lucidi, A.; Hailu, G.S.; Nebbioso, A.; Carafa, V.; Baratta, F.; Altucci, L.; Giacché, N.; Passeri, D.; et al. Development of 1,2,4-Oxadiazoles as Potent and Selective Inhibitors of the Human Deacetylase Sirtuin 2: Structure–Activity Relationship, X-ray Crystal Structure, and Anticancer Activity. J. Med. Chem. 2017, 60, 2344–2360.
    42. Avanzo, R.E.; Padrón, J.M.; D’Accorso, N.B.; Fascio, M.L. Synthesis and in vitro antiproliferative activities of (5-aryl-1,2,4-oxadiazole-3-yl) methyl D-ribofuranosides. Bioorg. Med. Chem. Lett. 2017, 27, 3674–3677.
    43. Abd el hameid, M.K.; Mohammed, M.R. Design, synthesis, and cytotoxicity screening of 5-aryl-3-(2-(pyrrolyl) thiophenyl)-1, 2, 4-oxadiazoles as potential antitumor molecules on breast cancer MCF-7 cells. Bioorg. Chem. 2019, 86, 609–623.
    44. de Oliveira, V.N.M.; dos Santos, F.G.; Ferreira, V.P.G.; Araújo, H.M.; do Ó Pessoa, C.; Nicolete, R.; de Oliveira, R.N. Focused microwave irradiation-assisted synthesis of N-cyclohexyl-1,2,4-oxadiazole derivatives with antitumor activity. Synth. Commun. 2018, 48, 2522–2532.
    45. Sateesh Kumar, P.; Umadevi, P. Novel Bis(1,2,4-oxadiazolyl) Fused Thiazole Derivatives: Synthesis and Anticancer Activity. Russ. J. Gen. Chem. 2018, 88, 2611–2615.
    46. Pervaram, S.; Ashok, D.; Sarasija, M.; Reddy, C.V.R.; Sridhar, G. Synthesis and Anticancer Activity of 1,2,4-Oxadiazole Fused Benzofuran Derivatives. Russ. J. Gen. Chem. 2018, 88, 1219–1223.
    47. Chakrapani, B.; Ramesh, V.; Pourna Chander Rao, G.; Ramachandran, D.; Madhukar Reddy, T.; Kalyan Chakravarthy, A.; Sridhar, G. Synthesis and Anticancer Evaluation of 1,2,4-Oxadiazole Linked Imidazothiadiazole Derivatives. Russ. J. Gen. Chem. 2018, 88, 1020–1024.
    48. Srinivas, M.; Satyaveni, S.; Ram, B. Synthesis and Anticancer Activity of 1,2,4-Oxadiazol Linked Benzimidazole Derivatives. Russ. J. Gen. Chem. 2018, 88, 2653–2657.
    49. Chiacchio, M.A.; Legnani, L.; Campisi, A.; Paola, B.; Giuseppe, L.; Iannazzo, D.; Veltri, L.; Giofrè, S.; Romeo, R. 1,2,4-Oxadiazole-5-ones as analogues of tamoxifen: Synthesis and biological evaluation. Org. Biomol. Chem. 2019, 17, 4892–4905.
    50. Krasavin, M.; Shetnev, A.; Sharonova, T.; Baykov, S.; Tuccinardi, T.; Kalinin, S.; Angeli, A.; Supuran, C.T. Heterocyclic periphery in the design of carbonic anhydrase inhibitors: 1,2,4-Oxadiazol-5-yl benzenesulfonamides as potent and selective inhibitors of cytosolic hCA II and membrane-bound hCA IX isoforms. Bioorg. Chem. 2018, 76, 88–97.
    51. Krasavin, M.; Shetnev, A.; Sharonova, T.; Baykov, S.; Kalinin, S.; Nocentini, A.; Sharoyko, V.; Poli, G.; Tuccinardi, T.; Presnukhina, S.; et al. Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment. Eur. J. Med. Chem. 2019, 164, 92–105.
    52. Cascioferro, S.; Attanzio, A.; Di Sarno, V.; Musella, S.; Tesoriere, L.; Cirrincione, G.; Diana, P.; Parrino, B. New 1,2,4-Oxadiazole Nortopsentin Derivatives with Cytotoxic Activity. Mar. Drugs 2019, 17, 35.
    53. Polothi, R.; Raolji, G.S.B.; Kuchibhotla, V.S.; Sheelam, K.; Tuniki, B.; Thodupunuri, P. Synthesis and biological evaluation of 1,2,4-oxadiazole linked 1,3,4-oxadiazole derivatives as tubulin binding agents. Synth. Commun. 2019, 49, 1603–1612.
    54. Yang, F.; Shan, P.; Zhao, N.; Ge, D.; Zhu, K.; Jiang, C.s.; Li, P.; Zhang, H. Development of hydroxamate-based histone deacetylase inhibitors containing 1,2,4-oxadiazole moiety core with antitumor activities. Bioorg. Med. Chem. Lett. 2019, 29, 15–21.
    55. Yang, F.; Zhang, T.; Wu, H.; Yang, Y.; Liu, N.; Chen, A.; Li, Q.; Li, J.; Qin, L.; Jiang, B.; et al. Design and Optimization of Novel Hydroxamate-Based Histone Deacetylase Inhibitors of Bis-Substituted Aromatic Amides Bearing Potent Activities against Tumor Growth and Metastasis. J. Med. Chem. 2014, 57, 9357–9369.
    56. Yang, Z.; Shen, M.; Tang, M.; Zhang, W.; Cui, X.; Zhang, Z.; Pei, H.; Li, Y.; Hu, M.; Bai, P.; et al. Discovery of 1,2,4-oxadiazole-Containing hydroxamic acid derivatives as histone deacetylase inhibitors potential application in cancer therapy. Eur. J. Med. Chem. 2019, 178, 116–130.
    57. Han, M.; Li, S.; Ai, J.; Sheng, R.; Hu, Y.; Hu, Y.; Geng, M. Discovery of 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides as novel RET kinase inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 5679–5684.
    58. Hande, K. Etoposide: Four decades of development of a topoisomerase II inhibitor. Eur. J. Cancer 1998, 34, 1514–1521.
    59. Guest, J.F.; Panca, M.; Sladkevicius, E.; Gough, N.; Linch, M. Cost Effectiveness of First-Line Treatment with Doxorubicin/Ifosfamide Compared to Trabectedin Monotherapy in the Management of Advanced Soft Tissue Sarcoma in Italy, Spain, and Sweden. Sarcoma 2013, 2013, 1–19.
    60. Carvalho, C.; Santos, R.; Cardoso, S.; Correia, S.; Oliveira, P.; Santos, M.; Moreira, P. Doxorubicin: The Good, the Bad and the Ugly Effect. Curr. Med. Chem. 2009, 16, 3267–3285.
    61. Avanzo, R.E.; Anesini, C.; Fascio, M.L.; Errea, M.I.; D’Accorso, N.B. 1,2,4-Triazole D-ribose derivatives: Design, synthesis and antitumoral evaluation. Eur. J. Med. Chem. 2012, 47, 104–110.
    62. Woolhouse, M.E.; Gowtage-Sequeria, S. Host Range and Emerging and Reemerging Pathogens. Emerg. Infect. Dis. 2005, 11, 1842–1847.
    63. Dye, C. After 2015: Infectious diseases in a new era of health and development. Philos. Trans. R. Soc. B Biol. Sci. 2014, 369, 20130426.
    64. Lozano, R.; Naghavi, M.; Foreman, K.; Lim, S.; Shibuya, K.; Aboyans, V.; Abraham, J.; Adair, T.; Aggarwal, R.; Ahn, S.Y.; et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012, 380, 2095–2128.
    65. O’Daniel, P.I.; Peng, Z.; Pi, H.; Testero, S.A.; Ding, D.; Spink, E.; Leemans, E.; Boudreau, M.A.; Yamaguchi, T.; Schroeder, V.A.; et al. Discovery of a New Class of Non-β-lactam Inhibitors of Penicillin-Binding Proteins with Gram-Positive Antibacterial Activity. J. Am. Chem. Soc. 2014, 136, 3664–3672.
    66. Carter, G.P.; Harjani, J.R.; Li, L.; Pitcher, N.P.; Nong, Y.; Riley, T.V.; Williamson, D.A.; Stinear, T.P.; Baell, J.B.; Howden, B.P. 1,2,4-Oxadiazole antimicrobials act synergistically with daptomycin and display rapid kill kinetics against MDR Enterococcus faecium. J. Antimicrob. Chemother. 2018, 73, 1562–1569.
    67. Ding, D.; Boudreau, M.A.; Leemans, E.; Spink, E.; Yamaguchi, T.; Testero, S.A.; O’Daniel, P.I.; Lastochkin, E.; Chang, M.; Mobashery, S. Exploration of the structure–activity relationship of 1,2,4-oxadiazole antibiotics. Bioorg. Med. Chem. Lett. 2015, 25, 4854–4857.
    68. Spink, E.; Ding, D.; Peng, Z.; Boudreau, M.A.; Leemans, E.; Lastochkin, E.; Song, W.; Lichtenwalter, K.; O’Daniel, P.I.; Testero, S.A.; et al. Structure–Activity Relationship for the Oxadiazole Class of Antibiotics. J. Med. Chem. 2015, 58, 1380–1389.
    69. Leemans, E.; Mahasenan, K.V.; Kumarasiri, M.; Spink, E.; Ding, D.; O’Daniel, P.I.; Boudreau, M.A.; Lastochkin, E.; Testero, S.A.; Yamaguchi, T.; et al. Three-Dimensional QSAR Analysis and Design of New 1,2,4-Oxadiazole Antibacterials. Bioorg. Med. Chem. Lett. 2016, 26, 1011–1015.
    70. Xiao, Q.; Vakulenko, S.; Chang, M.; Mobashery, S. Mutations in mmpL and in the Cell Wall Stress Stimulon Contribute to Resistance to Oxadiazole Antibiotics in Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2014, 58, 5841–5847.
    71. Janardhanan, J.; Chang, M.; Mobashery, S. The oxadiazole antibacterials. Curr. Opin. Microbiol. 2016, 33, 13–17.
    72. Ceballos, S.; Kim, C.; Ding, D.; Mobashery, S.; Chang, M.; Torres, C. Activities of Oxadiazole Antibacterials against Staphylococcus aureus and Other Gram-Positive Bacteria. Antimicrob. Agents Chemother. 2018, 62.
    73. Krolenko, K.Y.; Vlasov, S.V.; Zhuravel, I.A. Synthesis and antimicrobial activity of 5-(1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazole derivatives. Chem. Heterocycl. Compd. 2016, 52, 823–830.
    74. Cunha, F.; Nogueira, J.; de Aguiar, A. Synthesis and Antibacterial Evaluation of 3,5-Diaryl-1,2,4-oxadiazole Derivatives. J. Braz. Chem. Soc. 2018, 29, 2405–2416.
    75. Shi, G.; He, X.; Shang, Y.; Xiang, L.; Yang, C.; Han, G.; Du, B. Synthesis of 3′,4′-Diaryl-4′H -spiro[indoline-3,5′-[1′,2′,4′]oxadiazol]-2-ones via DMAP-catalyzed Domino Reactions and Their Antibacterial Activity. Chin. J. Chem. 2016, 34, 901–909.
    76. Shetnev, A.; Baykov, S.; Kalinin, S.; Belova, A.; Sharoyko, V.; Rozhkov, A.; Zelenkov, L.; Tarasenko, M.; Sadykov, E.; Korsakov, M.; et al. 1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer. Int. J. Mol. Sci. 2019, 20, 1699.
    77. Tarasenko, M.; Sidneva, V.; Belova, A.; Romanycheva, A.; Sharonova, T.; Baykov, S.; Shetnev, A.; Kofanov, E.; Kuznetsov, M. An efficient synthesis and antimicrobial evaluation of 5-alkenyl- and 5-styryl-1,2,4-oxadiazoles. Arkivoc 2018, 2018, 458–470.
    78. Atmaram Upare, A.; Gadekar, P.K.; Sivaramakrishnan, H.; Naik, N.; Khedkar, V.M.; Sarkar, D.; Choudhari, A.; Mohana Roopan, S. Design, synthesis and biological evaluation of (E)-5-styryl-1,2,4-oxadiazoles as anti-tubercular agents. Bioorg. Chem. 2019, 86, 507–512.
    79. Shruthi, T.; Eswaran, S.; Shivarudraiah, P.; Narayanan, S.; Subramanian, S. Synthesis, antituberculosis studies and biological evaluation of new quinoline derivatives carrying 1,2,4-oxadiazole moiety. Bioorg. Med. Chem. Lett. 2019, 29, 97–102.
    80. dos Santos Filho, J.M.; de Queiroz e Silva, D.M.A.; Macedo, T.S.; Teixeira, H.M.P.; Moreira, D.R.M.; Challal, S.; Wolfender, J.L.; Queiroz, E.F.; Soares, M.B.P. Conjugation of N-acylhydrazone and 1,2,4-oxadiazole leads to the identification of active antimalarial agents. Bioorg. Med. Chem. 2016, 24, 5693–5701.
    81. Kim, J.; Shin, J.S.; Ahn, S.; Han, S.B.; Jung, Y.S. 3-Aryl-1,2,4-oxadiazole Derivatives Active Against Human Rhinovirus. ACS Med. Chem. Lett. 2018, 9, 667–672.
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