One-Step Construction of 1,3,4-Oxadiazoles with Anticancer Activity from Tertiary Amines via a Sequential Copper(I)-Catalyzed Oxidative Ugi/aza-Wittig Reaction.

An unparalleled copper(I)-catalyzed synthesis of 1,3,4-oxadiazoles from tertiary amines in one step has been described. The one-pot reactions involving (N-isocyanimine)triphenylphosphorane, tertiary amines, and carboxylic acids resulted in the formation of 1,3,4-oxadiazoles in moderate to good yields through a consecutive oxidative Ugi/aza-Wittig reaction, enabling the direct functionalization of sp3 C-H bonds adjacent to the nitrogen atom. This method offered several notable advantages, including ligands-free, exceptional productivity and a high functional group tolerance. The preliminary biological evaluation demonstrated that compound 4f inhibited hepatoma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

Design and Enantioselective Synthesis of Chiral Pyranone Fused Indole Derivatives with Antibacterial Activities against Xanthomonas oryzae pv oryzae for Protection of Rice.

A new class of chiral pyranone fused indole derivatives were prepared by means of N-heterocyclic carbene (NHC) organocatalysis and demonstrated notable antibacterial activity against Xanthomonas oryzae pv oryzae (Xoo). Bioassays showed that compounds (3S,4R)-5b, (3S,4R)-5d, and (3S,4R)-5l exhibited promising in vitro efficacy against Xoo, with EC50 values of 9.05, 9.71, and 5.84 mg/L, respectively, which were superior to that of the positive controls with commercial antibacterial agents, bismerthiazol (BT, EC50 = 27.8 mg/L) and thiodiazole copper (TC, EC50 = 70.1 mg/L). Furthermore, single enantiomer (3S,4R)-5l was identified as an optimal structure displaying 55.3% and 52.0% curative and protective activities against Xoo in vivo tests at a concentration of 200 mg/L, which slightly surpassed the positive control with TC (curative and protective activities of 47.2% and 48.8%, respectively). Mechanistic studies through molecular docking analysis revealed preliminary insights into the distinct anti-Xoo activity of the two single enantiomers (3S,4R)-5l and (3R,4S)-5l, wherein the (3S,4R)-configured stereoisomer could form a more stable interaction with XooDHPS (dihydropteroate synthase). These findings underscore the significant anti-Xoo potential of these chiral pyranone fused indole derivatives, and shall inspire further exploration as promising lead structures for a novel class of bactericides to combat bacterial infections and other plant diseases.

New daphnane diterpenoidal 1,3,4-oxdiazole derivatives as potential anti-hepatoma agents: Synthesis, biological evaluation and molecular modeling studies.

Hepatocellular carcinoma (HCC) is a major challenge for human healthy. Daphnane-type diterpenes have attracted increasingly attention due to remarkable pharmaceutical potential including anti-HCC activity. To further develop this class of compounds as inhibitors of HCC, the daphnane diterpenoids 12-O-debenzoyl-Yuanhuacine (YHC) and 12-hydroxydaphnetoxin (YHE) were prepared by a standard chemical transformation from dried flower buds of the Daphne genkwa plant. Subsequently, 22 daphnane diterpenoidal 1,3,4-oxdiazole derivatives were rationally designed and synthesized based on YHC and YHE. The assessment of the target compound's anti-hepatocellular carcinoma activity revealed that YHC1 exhibited comparable activity to sorafenib in the Hep3B cell line, while demonstrating higher selectivity. The mechanistic investigation demonstrates that compound YHC1 induces cell cycle arrest at the G0/G1 phase, cellular senescence, apoptosis, and elevates cellular reactive oxygen species levels. Moreover, molecular docking and CETSA results confirm the interaction between YHC1 and YAP1 as well as TEAD1. Co-IP experiments further validated that YHC1 can effectively inhibit the binding of YAP1 and TEAD1. In conclusion, YHC1 selectively targets YAP1 and TEAD1, exhibiting its anti-hepatocellular carcinoma effects through the inhibition of their interaction.

Bioinspired total synthesis and biological activity of Pegaharine A.

BACKGROUND: Phytopathogens cause various diseases by parasitizing crops, reducing crop yield and resulting in substantial economic losses in agricultural production. A novel type isolated from the perennial herbaceous Peganum harmala L. seeds, ß-carboline alkaloids pegaharine A (PA), has become a hot topic in developing plant-originated green pesticides owing to their significant physiological activities. RESULTS: A scalable bioinspired total synthesis of PA is accomplished in the present work. The systematical biological assay study showed that PA exhibited moderate inhibitory activity against nine tested plant pathogenic fungi and showed significant inhibitory activity in vitro against the three tested plant pathogenic bacteria. Most noteworthy is the inhibitory rates of PA on Xanthomonas oryzae pv. oryzae (Xoo), X. oryzae pv. oryzicola (Xoc) and X. axonopodis pv. citri (Xac) of 93.6%, 92.1% and 86.1%, respectively, which are better than the control drug, bismerthiazol (63.4%, 61.2% and 53.7% at 100 µg mL-1 concentration). Furthermore, the EC50 value of PA against Xoo, Xoc and Xac was 52.2, 60.0 and 65.1 µg mL-1 , respectively, superior to 72.9, 64.2 and 70.1 µg mL-1 of the control drug. Moreover, the anti-Xoo mechanistic studies revealed that PA exerted its antibacterial effects by increasing the permeability of the bacterial membrane, reducing the extracellular polysaccharide content and inducing morphological changes in bacterial cells. CONCLUSION: A novel ß-carboline alkaloid, PA, was prepared by biomimetic total synthesis. Its significant antibacterial activity was closely related to the permeation of bacterial cell membranes, which was confirmed by anti-Xoo mechanistic studies. More importantly, the structure could be regarded as a model for developing novel bactericides. © 2023 Society of Chemical Industry.

Unveiling the chemistry of 1,3,4-oxadiazoles and thiadiazols: A comprehensive review.

Oxadiazoles and thiadiazoles are malleable heterocycles that have recently generated major interest in the field of medicinal chemistry. Compounds based on these moieties have versatile biological applications such as anticonvulsant, anticancer, antidiabetic, and antioxidant agents. Due to the versatile nature and stability of the oxadiazole and thiadiazole nucleus, medicinal chemists have changed the structural elements of the ring in numerous ways. These compounds have shown significant anticonvulsant effects, demonstrating their potential in the management of epileptic disorders. In this review, we have covered numerous biological pathways and in silico targeted proteins of oxadiazole and thiadiazole derivatives for treating various biological disorders. The data compiled in this article will be helpful for researchers, research scientists, and research chemists who work in the field of drug discovery and drug development.

Both Nitro Groups Are Essential for High Antitubercular Activity of 3,5-Dinitrobenzylsulfanyl Tetrazoles and 1,3,4-Oxadiazoles through the Deazaflavin-Dependent Nitroreductase Activation Pathway.

3,5-Dinitrobenzylsulfanyl tetrazoles and 1,3,4-oxadiazoles, previously identified as having high in vitro activities against both replicating and nonreplicating mycobacteria and favorable cytotoxicity and genotoxicity profiles were investigated. First we demonstrated that these compounds act in a deazaflavin-dependent nitroreduction pathway and thus require a nitro group for their activity. Second, we confirmed the necessity of both nitro groups for antimycobacterial activity through extensive structure-activity relationship studies using 32 structural types of analogues, each in a five-membered series. Only the analogues with shifted nitro groups, namely, 2,5-dinitrobenzylsulfanyl oxadiazoles and tetrazoles, maintained high antimycobacterial activity but in this case mainly as a result of DprE1 inhibition. However, these analogues also showed increased toxicity to the mammalian cell line. Thus, both nitro groups in 3,5-dinitrobenzylsulfanyl-containing antimycobacterial agents remain essential for their high efficacy, and further efforts should be directed at finding ways to address the possible toxicity and solubility issues, for example, by targeted delivery.

Design, synthesis, and biological evaluation of a novel series of 1,2,4-oxadiazole inhibitors of SLACK potassium channels: Identification of in vitro tool VU0935685.

Malignant migrating partial seizure of infancy (MMPSI) is a devastating and pharmacoresistant form of infantile epilepsy. MMPSI has been linked to multiple gain-of-function (GOF) mutations in the KCNT1 gene, which encodes for a potassium channel often referred to as SLACK. SLACK channels are sodium-activated potassium channels distributed throughout the central nervous system (CNS) and the periphery. The investigation described here aims to discover SLACK channel inhibitor tool compounds and profile their pharmacokinetic and pharmacodynamic properties. A SLACK channel inhibitor VU0531245 (VU245) was identified via a high-throughput screen (HTS) campaign. Structure-activity relationship (SAR) studies were conducted in five distinct regions of the hit VU245. VU245 analogs were evaluated for their ability to affect SLACK channel activity using a thallium flux assay in HEK-293 cells stably expressing wild-type (WT) human SLACK. Selected analogs were tested for metabolic stability in mouse liver microsomes and plasma-protein binding in mouse plasma. The same set of analogs was tested via thallium flux for activity versus human A934T SLACK and other structurally related potassium channels, including SLICK and Maxi-K. In addition, potencies for selected VU245 analogs were obtained using whole-cell electrophysiology (EP) assays in CHO cells stably expressing WT human SLACK through an automated patch clamp system. Results revealed that this scaffold tolerates structural changes in some regions, with some analogs demonstrating improved SLACK inhibitory activity, good selectivity against the other channels tested, and modest improvements in metabolic clearance. Analog VU0935685 represents a new, structurally distinct small-molecule inhibitor of SLACK channels that can serve as an in vitro tool for studying this target.

Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6.

Histone deacetylase 6 (HDAC6) is an important drug target in oncological and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize hydroxamic acids as a zinc-binding group, which limits therapeutic opportunities due to its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6.

Novel pyrimidine-1,3,4-oxadiazole hybrids and their precursors as potential antimycobacterial agents.

Background: Molecular hybridization and isostery are proven approaches in medicinal chemistry, and as such we used them to design novel compounds that we investigated as potential antimycobacterials to combat drug-resistant strains. Methods & results: Prepared N-alkyl-2-(pyrimidine-5-carbonyl)hydrazine-1-carboxamides were cyclized to N-alkyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amines along with their analogues. A total of 48 compounds were tested against Mycobacterium tuberculosis H37Rv, Mycobacterium avium and Mycobacterium kansasii, with oxadiazoles and C8-C12 alkyls being the most effective from a concentration of 2 µM. Multidrug-resistant strains were inhibited at same concentrations as the susceptible strain. For the most potent N-dodecyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amine, the mechanism of action related to cell wall biosynthesis was investigated. Conclusion: Pyrimidine-1,3,4-oxadiazole hybrids are unique antimycobacterial agents inhibiting mainly M. tuberculosis strains without cross-resistance to current drugs and are thus promising drug candidates.

Short pathways to highly active antimicrobial: structurally diverse polyamines derivatives from Amino-Aldehyde condensation strategy.

BACKGROUND: Chemical fungicides are the mainstay of plant disease control in agricultural production, but there are a very limited number of drugs that can effectively control plant diseases. Two series of secondary amine derivatives were synthesized using the diamine skeleton combined with saturated aromatic and aliphatic aldehydes, and their antibacterial and antifungal activities against plant pathogens were determined. In addition, the antimicrobial mechanism of the highly active compound A26 was preliminarily examined against Xanthomonas oryzae (Xoo). RESULTS: Compound A26 exhibited the highest antibacterial potency among all the target compounds, with MIC values of 3.12, 3.12 and 12.5 µg mL-1 against Xoo, Xanthomonas axonopodis pv. Citri and Pseudomonas sollamacearum, respectively. In addition, compound A26 had powerful curative and protective effects against Xoo at 200 µg mL-1 , and was better than the control agent Xinjunan. Preliminary mechanistic studies showed that compound A26 reduced the bacterial pathogenicity by targeting cell membranes and inhibiting the secretion of extracellular polysaccharides. Meanwhile, the toxicity of compound A26 to Human Embryonic Kidney 293 cells and Human Liver-7702 was similar to that of Xinjunan, and it had moderate toxicity according to the World Health Organization classification standard of oral exogenous toxicity, with an LD50 of 245.47 mg kg-1 . CONCLUSION: Secondary amines have efficient and broad-spectrum antibacterial activity against plant pathogenic bacteria and are expected to be a new class of candidate compounds for antibacterial drugs. © 2023 Society of Chemical Industry.

Discovery of Natural Sesquiterpene Lactone 1-O-Acetylbritannilactone Analogues Bearing Oxadiazole, Triazole, or Imidazole Scaffolds for the Development of New Fungicidal Candidates.

In recent decades, natural products have been considered important resources for developing of new agrochemicals because of their novel architectures and multibioactivities. Consequently, herein, 1-O-acetylbritannilactone (ABL), a natural sesquiterpene lactone from Inula britannica L., was used as a lead for further modification to discover fungicidal candidates. Six series of ABL-based derivatives containing an oxadiazole, triazole, or imidazole moiety were designed and synthesized, and their antifungal activities were also evaluated in vitro and in vivo. Bioassay results revealed that compounds 8d, 8h, and 8j (EC50 = 61.4, 30.9, and 12.4 µg/mL, respectively) exhibited more pronounced inhibitory activity against Fusarium oxysporum than their precursor ABL (EC50 > 500 µg/mL) and positive control hymexazol (EC50 = 77.2 µg/mL). Derivatives 8d and 11j (EC50 = 19.6 and 41.5 µg/mL, respectively) exhibited more potent antifungal activity toward Cytospora mandshurica than ABL (EC50 = 68.3 µg/mL). Compound 10 exhibited excellent and broad-spectrum antifungal activity against seven phytopathogenic fungal mycelia. Particularly, the inhibitory activity of compound 10 against the mycelium of Botrytis cinerea was more than 10.8- and 2.3-fold those of ABL and hymexazol, respectively. Meanwhile, derivative 10 (IC50 = 47.7 µg/mL) displayed more pronounced inhibitory activity against the spore of B. cinerea than ABL (IC50 > 500 µg/mL) and difenoconazole (IC50 = 80.8 µg/mL). Additionally, the in vivo control efficacy of compound 10 against B. cinerea was further studied using infected tomatoes (protective effect = 58.4%; therapeutic effect = 48.7%). The preliminary structure-activity relationship analysis suggested that the introduction of the 1,3,4-oxadiazole moiety (especially the 1,3,4-oxadiazole heterocycle containing the 4-chlorophenyl, 2-furyl, or 2-pyridinyl group) on the skeleton of ABL was more likely to produce potential antifungal compounds. These findings pave the way for further design and development of ABL-based derivatives as potential antifungal agents.

Discovery and Structural Optimization of 1,2,3,4-Tetrahydro-ß-carbolines as Novel Reactive Oxygen Species Inducers for Controlling Intractable Plant Bacterial Diseases.

Nowadays, reactive oxygen species (ROS) have been acknowledged as promising bactericidal targets against pesticide-resistant bacteria. Herein, to further excavate more excellent ROS inducers, simple 1,2,3,4-tetrahydro-ß-carboline derivatives containing a 3-aminopropanamide moiety were prepared and assessed for their antibacterial potency. Notably, three promising compounds displayed significant antibacterial potency. Compound I29 exhibits excellent in vitro bioactivity, with an EC50 value of 5.73 µg/mL, and admirable in vivo activities (protective activity of 55.74% and curative activity of 65.50%) toward Xanthomonas oryzae pv. oryzae. Compound I16 has good activity in vitro, with an EC50 of 3.43 µg/mL, and outstanding bioactivities in vivo (protective activity of 92.50% and curative activity of 59.68%) against Xanthomonas axonopodis pv. citri. Compound I6 shows excellent in vitro bioactivity (EC50 = 2.86 µg/mL) and significant protective activity (94.02%) for preventing Pseudomonas syringae pv. actinidiae. Antibacterial mechanism investigations indicate that these compounds disrupt the balance of the redox system to kill bacteria. These simple 1,2,3,4-tetrahydro-ß-carboline derivatives are promising leads to the discovery of bactericidal agents.

Multistep Synthesis of Analogues of Remdesivir: Incorporating Heterocycles at the C-1' Position.

Studies suggest that the 1'ß-CN moiety in remdesivir sterically clashes with the Ser861 residue of the RNA-dependent-RNA polymerase (RdRp), causing a delayed chain termination in the RNA replication process. Replacing C1'ß-CN with 5-membered heterocycles such as tetrazoles, oxadiazoles, and triazoles can augment the inhibitory activity and pharmacokinetic profile of C-nucleotides. Synthesis of tetrazole-, triazole-, and oxadiazole-integrated C1' analogues of remdesivir was attempted using general synthetic routes. The final compounds 26, 28, and 29 did not inhibit viral replication; however, the synthetic intermediates, i.e., 27 and 50, exhibited an IC90 = 14.1 µM each. The trifluoromethyl-substituted 1,2,4-oxadiazole 59 showed an IC90 of 33.5 µM. This work adds to the growing evidence of the beneficial medicinal impact of C1,1'-disubstituted C-nucleotides.

In-Silico Design, Synthesis, and Pharmacological Evaluation of Oxadiazole-Based Selective Cyclo-oxygenase-2 Inhibitors.

A series of oxadiazole-based five-membered heterocyclic derivatives was designed and synthesized with the intent of exclusive cyclo-oxygenase-2 (COX-2) inhibition to acquire anti-inflammatory activity without the presence of gastric toxicity. Oxadiazole-based novel analogs were designed by using bioisosteric substitutions and were screened against the macromolecular target by using docking-based virtual screening to identify their potential inhibitors. These selective COX-2 inhibitors were further evaluated for their stability within the binding cavity of macromolecular complex by performing molecular dynamic simulation for 100 ns. Selected compounds were synthesized by using Naphthalene-2-yl-acetic acid as a starting material based on the fundamental structure of naphthalene. The naphthalene ring and methylene bridge of naphthalene-2-yl-acetic acid were retained in the rational molecular design by replacing the carboxyl group with biologically significant groups like 1,3,4-oxadiazoles, with the goal of obtaining a novel, superior, and relatively safe anti-inflammatory molecule with better efficacy and optimized pharmacokinetics. Anti-inflammatory as well as analgesic properties of the compounds were evaluated experimentally for their pharmacological efficiency.

Design, Synthesis, Characterization and Computational Studies of Mannich Bases Oxadiazole Derivatives as New Class of Jack Bean Urease Inhibitors.

Mannich bases consisting of 1,3,4-oxadiazole-2-thione (3 a-3 l) bearing various substituents were synthesized and found potent jack bean urease inhibitors. The prepared compounds showed significantly good inhibitory activities with IC50 values from 9.45±0.05 to 267.42±0.23 µM. The compound 3 k containing 4-chlorophenyl (-R) and 4-hydroxyphenyl (-R') was most active with IC50 9.45±0.05 µM followed by 3 e (IC50 22.52±0.15 µM) in which -R was phenyl and -R' was isopropyl group. However, when both -R and -R' were either 4-chlorophenyl groups (3 l) or only -R' was 4-nitrophenyl (3 i), both compounds were found inactive. The detailed binding affinities of the produced compounds with protein were explored through molecular docking and data-supported in-vitro enzyme inhibition profiles. Drug likeness was confirmed by in silico ADME investigations and molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps were got from DFT calculations. ESP maps exposed that there are two potential binding sites with the most positive and most negative parts.

Design and synthesis of thiadiazole-oxadiazole-acetamide derivatives: Elastase inhibition, cytotoxicity, kinetic mechanism, and computational studies.

Considering the biological significance of 1,3,4-thiadiazole/oxadiazole heterocyclic scaffolds, a novel series of 1,3,4-thiadiazole-1,3,4-oxadiazole-acetamide derivatives (7a-j) was designed and synthesized using molecular hybridization. The inhibitory effects of the target compounds on elastase were evaluated, and all of these molecules were found to be potent inhibitors compared to the standard reference oleanolic acid. Compound 7f exhibited the excellent inhibitory activity (IC50 = 0.06 ± 0.02 µM), which is 214-fold more active than oleanolic acid (IC50 = 12.84 ± 0.45 µM). Kinetic analysis was also performed on the most potent compound (7f) to determine the mode of binding with the target enzyme, and it was discovered that 7f inhibits the enzyme in a competitive manner. Furthermore, the MTT assay method was used to assess their toxicity on the viability of B16F10 melanoma cell lines, and all compounds did not display any toxic effect on the cells even at high concentrations. The molecular docking studies of all compounds also justified with their good docking score and among them, compound 7f had a good conformational state with hydrogen bond interactions within the receptor binding pocket, which is consistent with the experimental inhibition studies.

Pyrimido[4,5-b]indole derivatives bearing 1,2,4-oxadiazole moiety as MDM2 inhibitor candidates in cancer treatment.

Aim: In this study, novel hybrid structures of pyrimido-indole-oxadiazole were developed as MDM2 inhibitors for restoring the regular function of the p53. Materials & methods: A multistep chemical pathway was used to synthesize the derivatives. Nutlin-3a was used as a standard lead in molecular docking and molecular dynamics simulations. Finally, cytotoxicity was evaluated against MCF-7 cancer cells versus Doxorubicin. Results: The most promising candidate was 12c, which had an NO2 group in the para position of the oxadiazole ring (IC50: 1.1 µM). A satisfactory result was obtained with the combined application of 12c and Doxorubicin (IC50 decreased to 0.63 µM), which could be potentially attributed to MDM2 inhibition. Conclusion: These hybrid structures can be further investigated as potential MDM2 inhibitors.

Rapid Assembly of Pyrrole-Ligated 1,3,4-Oxadiazoles and Excellent Antibacterial Activity of Iodophenol Substituents.

Pyrrole-ligated 1,3,4-oxadiazole is a very important pharmacophore which exhibits broad therapeutic effects such as anti-tuberculosis, anti-epileptic, anti-HIV, anti-cancer, anti-inflammatory, antioxidant, and antibacterial activities. A one-pot Maillard reaction between D-Ribose and an L-amino methyl ester in DMSO with oxalic acid at 2.5 atm and 80 °C expeditiously produced pyrrole-2-carbaldehyde platform chemicals in reasonable yields, which were utilized for the synthesis of pyrrole-ligated 1,3,4-oxadiazoles. Benzohydrazide reacted with the formyl group of the pyrrole platforms to provide the corresponding imine intermediates, which underwent I2-mediated oxidative cyclization to the pyrrole-ligated 1,3,4-oxadiazole skeleton. The structure and activity relationship (SAR) of the target compounds with varying alkyl or aryl substituents of the amino acids and electron-withdrawing or electron-donating substituents on the phenyl ring of benzohydrazide were evaluated for antibacterial activity against Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii as representative Gram(-) and Gram(+) bacteria. Branched alkyl groups from the amino acid showed better antibacterial activities. Absolutely superior activities were observed for 5f-1 with an iodophenol substituent against A. baumannii (MIC < 2 µg/mL), a bacterial pathogen that displays a high resistance to commonly used antibiotics.

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles.

1,2,4-Oxadiazole is an essential motif in drug discovery represented in many experimental, investigational, and marketed drugs. This review covers synthetic methods that allow the conversion of different types of organic compounds into 1,2,4-oxadiazole at ambient temperature and the practical application of the latter approaches for the preparation of pharmaceutically important molecules. The discussed methods are divided into three groups. The first combines two-stage protocols requiring the preliminary preparation of O-acylamidoximes followed by cyclization under the action of organic bases. The advantages of this route are its swiftness, high efficiency of the cyclization process, and uncomplicated work-up. However, it requires the preparation and isolation of O-acylamidoximes as a separate preliminary step. The second route is a one-pot synthesis of 1,2,4-oxadiazoles directly from amidoximes and various carboxyl derivatives or aldehydes in aprotic bipolar solvents (primarily DMSO) in the presence of inorganic bases. This recently proposed pathway proved to be highly efficient in the field of medicinal chemistry. The third group of methods consists of diverse oxidative cyclizations, and these reactions have found modest application in drug design thus far. It is noteworthy that the reviewed methods allow for obtaining 1,2,4-oxadiazoles with thermosensitive functions and expand the prospects of using the oxadiazole core as an amide- or ester-like linker in the design of bioactive compounds.

Design, Synthesis and Bioactivity Evaluation of Novel 2-(pyrazol-4-yl)-1,3,4-oxadiazoles Containing an Imidazole Fragment as Antibacterial Agents.

Imidazole alkaloids, a common class of five-membered aromatic heterocyclic compounds, exist widely in plants, animals and marine organisms. Because of imidazole's extensive and excellent biological and pharmacological activities, it has always been a topic of major interest for researchers and has been widely used as an active moiety in search of bioactive molecules. To find more efficient antibacterial compounds, a series of novel imidazole-fragment-decorated 2-(pyrazol-4-yl)-1,3,4-oxadiazoles were designed and synthesized based on our previous works via the active substructure splicing principle, and their bioactivities were systematically evaluated both in vitro and in vivo. The bioassays showed that some of the target compounds displayed excellent in vitro antibacterial activity toward three virulent phytopathogenic bacteria, including Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas axonopodis pv. citri (Xac) and Pseudomonas syringae pv. actinidiae (Psa), affording the lowest EC50 values of 7.40 (7c), 5.44 (9a) and 12.85 (9a) µg/mL, respectively. Meanwhile, compound 7c possessed good in vivo protective and curative activities to manage rice bacterial leaf blight at 200 µg/mL, with control efficacies of 47.34% and 41.18%, respectively. Furthermore, compound 9a showed commendable in vivo protective and curative activities to manage kiwifruit bacterial canker at 200 µg/mL, with control efficacies of 46.05% and 32.89%, respectively, which were much better than those of the commercial bactericide TC (31.58% and 17.11%, respectively). In addition, the antibacterial mechanism suggested that these new types of title compounds could negatively impact the cell membranes of phytopathogenic bacteria cells and cause the leakage of the intracellular component, thereby leading to the killing of bacteria. All these findings confirm that novel 2-(pyrazol-4-yl)-1,3,4-oxadiazoles containing an imidazole fragment are promising lead compounds for discovering new bactericidal agents.