Synthetic Approaches and Pharmacological Activity of 1,3,4-Oxadiazoles: A Review of the Literature from 2000–2012

This review provides readers with an overview of the main synthetic methodologies for 1,3,4-oxadiazole derivatives, and of their broad spectrum of pharmacological activities as reported over the past twelve years.

Taking into account the importance of these compounds to both heterocyclic and medicinal chemistry, we have decided to present the main synthesis approaches used for obtaining the heterocyclic nucleus, as well as the broad spectrum of pharmacological activities reported in the literature over the past twelve years.

Antimicrobial Activity
The recent emergence of drug resistance when treating infectious diseases has underlined the need for new, safer, and more efficient antimicrobial agents. Many researchers have reported excellent antimicrobial activity for compounds containing the 1,3,4-oxadiazole core.
Recently, Oliveira and co-workers [64] reported synthesis and antistaphylococcal activity of 1,3,4-oxadiazolines 102 against strains of Staphylococcus aureus, resistant to methicillin and amino glycosides (MARSA), and that encode efflux proteins (multidrug drugs resistant-MDR). The compounds 102 showed efficient antistaphylococcal activity at 4 to 32 μg/mL, making all the compounds 2-8 times more active than the standard drug chloramphenicol ( Figure 5).

Anti-inflammatory Activity
A series of oxadiazole derivatives 138 of ibuprofen which contains the arylpiperazine unit at position 3 of the oxadiazole ring were investigated by Manjunatha and co-workers [20] for anti-inflammatory activity using paw edema induced by carrageenan as the method with sodium diclofenac as the reference. Compounds containing 4-Cl, 4-NO 2 , 4-F and 3-Cl groups were more active than sodium diclofenac, whereas compounds with 4-MeO and 2-EtO groups showed less activity (Figure 8). Compounds 139 were synthesized from the anti-inflammatory drug fenbufen and evaluated for anti-inflammatory activity by carrageenan induced paw edema; sodium diclofenac and fenbufen were the standards. The compounds containing 4-Cl, 4-NO 2 , 4-F and 4-MeO groups were equipotent to fenbufen, and the compound with a 3,4-di-MeO group was more potent than the fenbufen, and equal to sodium diclofenac [90] (Figure 8).
Ouyang and co-workers [104], and Tuma and co-workers [105] synthesized and evaluated various 1,3,4-oxadiazole derivatives as to their ability to inhibit tubulin polymerization and block the mitotic division of tumor cells. Compounds 154 and 155 exhibited potent activity. In vitro studies of compound 154 indicated that at nano-concentrations it interrupted mitotic division in breast carcinoma and squamous cell tumors, which included multi-drug resistant cells. In vivo studies of compound 155 displayed a desirable pharmacokinetic profile (with appropriate plasma levels after oral administration), and was significantly more effective than the taxane paclitaxel ( Figure 10).

Antiviral Activity
On October 16, 2007, the US Food and Drug Administration (FDA) approved raltegravir (Isentress ® , 162, Figure 11) for treatment of human immunodeficiency virus (HIV)-1 infection, in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication, and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is the prototype of a new class of antiretroviral drugs known as integrase inhibitors [110].
Seeking to identify more promising compounds than raltegravir, Wang and co-workers [111] synthesized a series of raltegravir derivatives by modifying the 5-hydroxyl group of the pyrimidine ring and evaluated them for anti-HIV activity. The 5-hydroxyl modification of raltegravir derivatives significantly increased their activity, which indicates the 5-hydroxyl group's dispensability. Compound 163 with a sub-picomol IC 50 value was the most potent anti-HIV agent among all of the derivatives synthesized, and thus emerged as a new and potent anti-HIV agent ( Figure 11). The inhibitory activity of the compounds 164 and 165 ( Figure 12) against the human immunodeficiency virus type 1 (HIV-1) was determined using the XTT assay on MT-4 cells. Compound 165 was the most active among the compounds tested, producing 100, 43 and 37% reductions in viral replication at concentrations of 50, 10 and 2 µg/mL respectively. Compounds 164 with R=4-F, and 2-Br groups exhibited less anti-viral replication activity yet above 10% inhibition at concentrations of 2 µg/mL. All tested compounds were non-cytotoxic with CD 50 > 100 µg/mL except compound 165 whose CD 50 was 68 µg/mL [112].
Iqbal and co-workers [113] reported inhibitory activity for compounds 166 and 167 ( Figure 12) against the human immunodeficiency virus type 1 (HIV-1) which was also determined using the XTT assay on MT-4 cells. Compound 166 with the R=Cl group was the most active among the compounds tested, with 62, 21 and 14% reductions at concentrations of 50, 25 and 5 μg/mL, respectively. Indinavir, another protease inhibitor is also used as a component of antiretroviral therapy for treating HIV infection and AIDS. Kim and co-workers [114] have synthesized and evaluated the protease inhibitory activity of a series of oxadiazoles 168 analogous to indinavir. All the compounds prepared inhibited protease activity at picomolar (IC 50 ) concentrations (thus being more potent than the indinavir) ( Figure 13).

Enzyme Inhibitors
Leukotrienes (LTs) are potent inflammatory lipid mediators derived from arachidonic acid metabolism, and released from cells involved in inflammation. The synthesis of all LTs requires the action of the enzyme 5-lipoxygenase (5-LO). Inhibition of 5-LO reduces the production of both LTB 4, and cysteinyl LTs (CysLTs); LTC 4 , LTD 4 and LTE 4 . 5-LO inhibitors have therapeutic potential for the treatment of inflammatory processes. A new oxadiazole p-toluenesulfonate derivative 173 (Figure 15) containing an asymmetric carbon was identified as both a potent and selective inhibitor of 5-lipoxygenase (5-LO) by Ducharme and co-workers [120], and Gosselin and co-workers [121].
Tomi and co-workers [124] reported a study with the bis-1,3,4-oxadiazole compound 176 that contains a glycine unit on the transferase activity of enzymes such as: GOT, GPT and γ-GT in serum. Compound 176 showed activation for GOT and GPT and inhibitory effects on the activity of γ-GT, (Figure 15). Maccioni and co-workers [125] synthesized a set of 3-acetyl-2,5-diaryl-2,3-dihydro-1,3,4oxadiazoles and tested them as inhibitors of human monoamine oxidase (MAO) A and B isoforms. None of the tested compounds displayed significant inhibitory ability for MAO-A. However, several compounds were identified as selective MAO-B inhibitors. Some of the tested compounds exhibit interesting biological properties with an IC 50 for the B isoform ranging from micromolar to nanomolar values. Compounds 177 were active at inhibiting MAO-B at nanomolar concentrations ( Figure 16).

Conclusions
This review, has summarized the synthetic methods and biological activities for 1,3,4-oxadiazole derivatives reported in the literature during the past twelve years. The main synthetic methods include: (1) cyclodehydration reactions of diacylhydrazines; (2) cyclization oxidative reactions of N-acylhydrazones; (3) the one-step synthesis from readily available carboxylic acids and acid hydrazides; (4) the reactions of hydrazides with orthoesters; (5) hydrazide reactions with carbon disulfide in basic medium; (6) reaction of tetrazoles with acid chloride or acid anhydride. Most research groups are still using these synthetic routes making use only of new reaction conditions such as: new cyclization reagents, new catalysts, polymeric supports and microwave radiation. Few innovative methods have emerged in recent years, highlighting the methods described by Ramazani and Rezaei [51] and Cui and co-workers [50]. Furthermore, the various synthetic methods exemplified may serve as a support for the planning of new molecules containing the 1,3,4-oxadiazole unit. The broad pharmacological profile of this class of compounds is evidenced by the numerous examples cited here. In each biological activity topic, we have only provided selected examples of molecules with relevant activity being that these molecules may serve as prototypes for the development of more active derivatives.