Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1,3,4-oxadiazole scaffold as FabH inhibitors

Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold (4-21). Among these compounds, 4 and 7-21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-1,3,4-oxadiazole (11) with MIC of 1.56-3.13 μg/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-5-(2-methylbenzyl)-1,3,4-oxadiazole (12) with MIC of 1.56-6.25 μg/mL were most potent inhibitors of Escherichia coli FabH.     

Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties

A series of new benzenesulfonamides, most of which are chiral, incorporating 1, 3, 4-oxadiazole and amino acid moieties have been synthesized. Some of these compounds were screened for antimalarial activity and also evaluated for their ability to inhibit hem polymerization. The electrophoretic analysis indicated that one compound was effective in inhibiting the degradation of hemoglobin. The synthesized compounds were tested in mice infected with Plasmodium berghei. These derivatives have the potential for the development of novel antimalarial lead compounds.     

Synthesis and evaluation of 1,3,4-oxadiazole derivatives for development as broad-spectrum antibiotics

The reality and intensity of antibiotic resistance in pathogenic bacteria calls for the rapid development of new antimicrobial drugs. In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. Because trans-translation is absent in eukaryotes but necessary to avoid ribosomal stalling and therefore essential for bacterial survival, it is a promising target either for novel antibiotics or for improving the activities of the protein synthesis inhibitors already in use. Oxadiazole derivatives display strong bactericidal activity against a large number of bacteria, but their effects on trans-translation were recently questioned. In this work, a series of new 1,3,4-oxadiazole derivatives and analogs were synthesized and assessed for their efficiency as antimicrobial agents against a wide range of gram-positive and gram-negative pathogenic strains. Despite the strong antimicrobial activity observed in these molecules, it turns out that they do not target trans-translation in vivo, but they definitely act on other cellular pathways.     

Design,synthesis, in vivo,and in silico evaluation of new coumarin-1,2,4-oxadiazole hybrids as anticonvulsant agents

A novel series of coumarin-1,2,4-oxadiazole hybrids were designed, synthesized, and evaluated as anticonvulsant agents. The title compounds were easily synthesized from reaction of appropriate coumarins and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazole derivatives. In vivo anticonvulsant activity of the synthesized compounds were determined using pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures confirming that they were more effective against MES test than PTZ test. It should be noted that compounds 3b, 3c, and 3e showed the best activity in MES model which possessed drug-like properties with no neurotoxicity. Anticonvulsant activity of the most potent compound 3b was remarkably reduced after treatment with flumazenil which confirmed the participation of a benzodiazepine mechanism in the anticonvulsant activity. Also, docking study of compound 3b in the BZD-binding site of GABA_A receptor confirmed possible binding of 3b to the BZD receptors.     

Comparison of anti-aggregatory activities of 5-phenyl-3-(3-pyridyl)isoxazole and 5-phenyl-3-(3-pyridyl)-1,2,4-oxadiazole

Two bioisosteric analogs, 5-phenyl-3-(3-pyridyl)isoxazole and 5-phenyl-3-(3-pyridyl)-1,2,4-oxadiazole, were synthesized so as to compare their antiaggregatory activities, to determine a pharmacologically active fragment in molecules of this type, and to explore the mechanisms of action of potential antiag-gregatory compounds belonging to the class of 3,5-substituted isoxazoles. Antiaggregatory activities of these compounds were studied in vitro using three aggregation inducers, such as arachidonic acid, adenosine diphosphate, and adrenaline. It was shown that 5-phenyl-3-(3-pyridyl)-1,2,4-oxadiazole and 5-phenyl-3-(3-pyridyl)isoxazole completely suppressed platelet aggregation induced by arachidonic acid and the second wave of platelet aggregation induced by adrenaline or adenosine diphosphate. The antiaggregatory activity of substituted isoxasole was 1.1–1.5 times higher than that of substituted oxadiazole. In contrast to the isoxazole analog, 5-phenyl-3-(3-pyridyl)-1,2,4-oxadiazole in concentrations of 300–400 μM partially suppressed the first wave of aggregation induced by adenosine diphosphate. It was demonstrated that both compounds were not thrombin inhibitors in vitro at concentrations up to 250 μM. Thus, introduction of a nitrogen atom into the C4-position of the isoxazole ring changes the molecule properties. It suggests that the pharmacophoric fragment of the molecule should be the whole isoxazole or 1,2,4-oxadiazole ring but not a part of the ring as was supposed previously.     

Natural Product‐Based Fungicides Discovery: Design,Synthesis and Antifungal Activities of Some Sarisan Analogs Containing 1,3,4‐Oxadiazole Moieties

A series of sarisan analogs containing 1,3,4‐oxadiazole moieties were synthesized by iodine‐mediated oxidative cyclization and screened in vitro for their antifungal activities at 50 μg/mL against five phytopathogenic fungi such as Valsa mali, Curvularia lunata, Alternaria alternate, Fusarium solani and Fusarium graminearum. 1,3,4‐Oxadiazole derivatives 7e , 7p , 7r , 7t and 7u exhibited potent and a broad spectrum of antifungal activities against at least three phytopathogenic fungi at the concentration of 50 μg/mL. Especially, compound 7r displayed more potent antifungal activities against five phytopathogenic fungi than the positive control hymexazol. The EC₅₀ of 7r against V. mali, C. lunata and A. alternate were 12.6, 14.5 and 17.0 μg/mL, respectively. Additionally, some interesting results of structure‐activity relationships (SARs) were also observed.     

Design,synthesis and anticancer activities evaluation of novel 5H-dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-oxadiazole units

Rucaparib and PJ34 were used as the structural model for the design of novel 5H-dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-oxadiazole units. And target compounds were successfully synthesized through a 3-step synthetic strategy. All target compounds were screened for their anti-proliferative effects against OVCAR-3 cell line. Preliminary biological study of these compounds provided potent compounds d21 and d22 with better activities than Rucaparib.     

Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator

To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase activation in vitro. In all cases, three carbon spacer between the oxadiazole core and one of the phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the oxadiazole and other phenyl ring are favorable. Introduction of hydrogen bonding donor (NH) group at the 2^nd position of the 1,3,4-oxadiazole enhances the activity. Substitutions on either of the phenyl rings or change of phenyl ring to other heterocycle are not tolerated for both the oxadiazoles. The prepared oxadiazoles showed selective activation for cardiac muscle over smooth and skeleton muscles.     

Diaryl-1,2,4-oxadiazole antioxidants: Synthesis and properties of inhibiting the oxidation of DNA and scavenging radicals

Six 1,2,4-oxadiazole derivatives were prepared in order to compare their abilities to protect DNA against radical-mediated oxidation and to scavenge radicals. These derivatives had a structure based on disubstituted 1,2,4-oxadiazole, in which a vanillin group (A ring) and a substituted benzene group (B ring) were the substituents. The functional group at B ring was assigned as ortho- or meta-hydroxylbenzene group, ortho-chlorobenzene group, no group contained, and pyridine group or vanillin group at B ring. It was found that the compound with two vanillin groups attaching to oxadiazole can trap 2.05 radicals in protecting DNA against 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation, and the compound with an ortho-hydroxylbenzene group at B ring can trap 1.78 radicals. The compound with an ortho-chlorobenzene group at B ring exhibited the highest ability to inhibit ^·OH-induced oxidation of DNA, while the compound with a meta-hydroxylbenzene group at B ring inhibited Cu²⁺/glutathione (GSH)-induced oxidation of DNA efficiently. The ortho- and para-hydroxylbenzene groups at B ring made the compounds possess the highest rate constant (k) in scavenging 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS^+.) and 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH). Therefore, only a few hydroxyl groups can markedly enhance the activity of the core-branched antioxidant, which may be a novel structural feature in designing antioxidant.     

In vitro anti-TB properties,in silico target validation,molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives (3a–3i) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound 3a with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively.To understand the mechanism of action of these compounds (3a–3i) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, in silico ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound 3a, promising leads worthy of further optimisation.     

Novel pyrazoline amidoxime and their 1,2,4-oxadiazole analogues: Synthesis and pharmacological screening

A novel series of pyrazoline amidoxime (2a–d) and pyrazoly-1,2,4-oxadiazole (3a–p) and (4) of pharmacological significance have been synthesised. Structures of newly synthesised compounds were characterized by spectral studies. New compounds were screened for their in vitro antioxidant, antimicrobial and antiinflammatory activities. Among the synthesized compounds, compound 2a, 3l and 3o were found to be active antimicrobial agents in addition to having potent antioxidant activity, while the compound 3f showed promising antiinflammatory activity in comparison with standard drug.     

Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity

Oxadiazole is a heterocyclic compound containing an oxygen atom and two nitrogen atoms in a five-membered ring. Of the four oxadiazoles known, 1,3,4-oxadiazole has become an important structural motif for the development of new drugs and the compounds containing 1,3,4-oxadiazole cores have a broad spectrum of biological activity. Herein, we describe the design, synthesis and biological evaluation of a series of novel 2,5-disubstituted 1,3,4-oxadiazoles (10a–10j) as class I histone deacetylase (HDAC) inhibitors. The compounds were designed and evaluated for HDAC8 selectivity using in silico docking software (Glide) and the top 10 compounds with high dock score and obeying Lipinski’s rule were synthesized organically. Further the biological HDAC inhibitory and selectivity assays and anti-proliferative assays were carried out. In in silico and in vitro studies, all compounds (10a–10j) showed significant HDAC inhibition and exhibited HDAC8 selectivity. Among all tested compounds, 10b showed substantial HDAC8 inhibitory activity and better anticancer activity which is comparable to the positive control, a FDA approved drug, vorinostat (SAHA). Structural activity relation is discussed with various substitutions in the benzene ring connected on 1,3,4-oxadizole and glycine/alanine. The study warranted further investigations to develop HDAC8-selective inhibitory molecule as a drug for neoplastic diseases. Novel 1,3,4-oxadizole substituted with glycine/alanine showed HDAC8 inhibition.     

Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety

A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC₅₀ value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC₅₀ values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC₅₀ values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.     

Design,synthesis, and antibacterial activity against rice bacterial leaf blight and leaf streak of 2,5-substituted-1,3,4-oxadiazole/thiadiazole sulfone derivative

A series of 2,5-substituted-1,3,4-oxadiazole/thiadiazole sulfone derivatives were synthesized and evaluated for their antibacterial activities against rice bacterial leaf blight and leaf streak caused by Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicolaby via the turbidimeter test in vitro. Antibacterial bioassay results indicated that most compounds demonstrated good inhibitory effect antibacterial bioactivities against rice bacterial leaf blight and leaf streak. Among the title compounds, compound 6c demonstrated the best inhibitory effect against rice bacterial leaf blight and leaf streak with half-maximal effective concentration (EC₅₀) values of 1.07 and 7.14 μg/mL, respectively, which were even better than those of commercial agents such as Bismerthiazol and Thiediazole Copper. In vivo antibacterial activities tests at greenhouse conditions demonstrated that the controlling effect of compounds 6c (43.5%) and 6g (42.4%) against rice bacterial leaf blight were better than those of Bismerthiazol (25.5%) and Thiediazole Copper (37.5%).     

Identification and optimization of novel 1,3,4-oxadiazole EP1 receptor antagonists

A novel series of oxadiazole EP1 receptor antagonists was identified by replacing the amide of a known glycine sulfonamide derivative with a 1,3,4-oxadiazole. Optimization of the substitution patterns on the three aromatic rings led to the identification of high affinity EP1 receptor antagonists. The derivative with highest affinity displayed a binding IC50 of 2.5 nM (pIC50 8.6).     

Synthesis and evaluation of 1,2,4-oxadiazole derivatives as potential anti-inflammatory agents by inhibiting NF-κB signaling pathway in LPS-stimulated RAW 264.7 cells

In this study, a series of compounds with 1,2,4-oxadiazole core was designed and synthesized for the optimization of JC01, an anti-inflammatory hit identified from our in-house compound library using NF-κB pathway luciferase assay and NO production assay. All the synthetic compounds 1–29 have been screened for their anti-inflammatory effects by evaluating their inhibition against LPS-induced NO release, and compound 17 exhibited the highest activity. Western blotting and immunofluorescence analysis revealed that 17 prominently inhibited LPS-induced activation of NF-κB in RAW264.7 cells and blocked the phosphorylation of p65. Consistent with these results, it was found that 17 prevented the nuclear translocation of NF-κB induced by LPS. These data highlighted 17 as a promising anti-inflammatory agent by inhibiting NF-κB activity.     

Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties

A series of new benzenesulfonamides, most of which are chiral, incorporating 1, 3, 4-oxadiazole and amino acid moieties have been synthesized. Some of these compounds were screened for antimalarial activity and also evaluated for their ability to inhibit hem polymerization. The electrophoretic analysis indicated that one compound was effective in inhibiting the degradation of hemoglobin. The synthesized compounds were tested in mice infected with Plasmodium berghei. These derivatives have the potential for the development of novel antimalarial lead compounds.     

Targeting malaria and leishmaniasis: Synthesis and pharmacological evaluation of novel pyrazole-1,3,4-oxadiazole hybrids. Part II

In continuance with earlier reported work, an extension has been carried out by the same research group. Mulling over the ongoing condition of resistance to existing antimalarial agents, we had reported synthesis and antimalarial activity of certain pyrazole-1,3,4-oxadiazole hybrid compounds. Bearing previous results in mind, our research group ideated to design and synthesize some more derivatives with varied substitutions of acetophenone and hydrazide. Following this, derivatives 5a–r were synthesized and tested for antimalarial efficacy by schizont maturation inhibition assay. Further, depending on the literature support and results of our previous series, certain potent compounds (5f, 5n and 5r) were subjected to Falcipain-2 inhibitory assay. Results obtained for these particular compounds further strengthened our hypothesis. Here, in this series, compound 5f having unsubstituted acetophenone part and a furan moiety linked to oxadiazole ring emerged as the most potent compound and results were found to be comparable to that of the most potent compound (indole bearing) of previous series. Additionally, depending on the available literature, compounds (5a–r) were tested for their antileishmanial potential. Compounds 5a, 5c and 5r demonstrated dose-dependent killing of the promastigotes. Their IC₅₀ values were found to be 33.3 ± 1.68, 40.1 ± 1.0 and 19.0 ± 1.47 μg/mL respectively. These compounds (5a, 5c and 5r) also had effects on amastigote infectivity with IC₅₀ of 44.2 ± 2.72, 66.8 ± 2.05 and 73.1 ± 1.69 μg/mL respectively. Further target validation was done using molecular docking studies. Acute oral toxicity studies for most active compounds were also performed.     

Synthesis of variously coupled conjugates of D-glucose, 1,3,4-oxadiazole, and 1,2,3-triazole for inhibition of glycogen phosphorylase

5-(O-Perbenzoylated-β-D-glucopyranosyl)tetrazole was obtained from O-perbenzoylated-β-D-glucopyranosyl cyanide by Bu(3)SnN(3) or Me(3)SiN(3)-Bu(2)SnO. This tetrazole was transformed into 5-ethynyl- as well as 5-chloromethyl-2-(O-perbenzoylated-β-D-glucopyranosyl)-1,3,4-oxadiazoles by acylation with propiolic acid-DCC or chloroacetyl chloride, respectively. The chloromethyl oxadiazole gave the corresponding azidomethyl derivative on treatment with NaN(3). These compounds were reacted with several alkynes and azides under Cu(I) catalysed cycloaddition conditions to give, after removal of the protecting groups by the Zemplén protocol, β-D-glucopyranosyl-1,3,4-oxadiazolyl-1,2,3-triazole, β-D-glucopyranosyl-1,2,3-triazolyl-1,3,4-oxadiazole, and β-D-glucopyranosyl-1,3,4-oxadiazolylmethyl-1,2,3-triazole type compounds. 5-Phenyltetrazole was also transformed under the above conditions into a series of aryl-1,3,4-oxadiazolyl-1,2,3-triazoles, aryl-1,2,3-triazolyl-1,3,4-oxadiazoles, and aryl-1,3,4-oxadiazolylmethyl-1,2,3-triazoles. The new compounds were assayed against rabbit muscle glycogen phosphorylase b and the best inhibitors had inhibition constants in the upper micromolar range (2-phenyl-5-[1-(β-D-glucopyranosyl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole 36: K(i)=854μM, 2-(β-D-glucopyranosyl)-5-[1-(naphthalen-2-yl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole 47: K(i)=745μM).     

Synthesis and biological evaluation of coumarin-1,3,4-oxadiazole hybrids as selective carbonic anhydrase IX and XII inhibitors

With an aim to develop novel heterocyclic hybrids as potent anticancer agents, we synthesized a series of coumarin-1,3,4-oxadiazole hybrids (7a-t) and evaluated for their inhibitory activity against the four physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms CA I, CA II, CA IX and CA XII. The CA inhibition results clearly indicated that the coumarin-1,3,4-oxadiazole derivatives (7a-t) exhibited selective inhibition of the tumor associated isoforms, CA IX and CA XII over CA I and II isoforms. Among all, compound 7b, exhibited significant inhibition in lower micromolar potency against hCA XII, with a K_i of 0.16 µM and compound 7n, exhibited significant inhibition in lower micromolar potency against hCA IX, with a K_i of 2.34 µM respectively. Therefore, compound 7b and 7n could be the potential leads for development of selective anticancer agents by exhibiting a novel mechanism of action through hCA IX and XII inhibition.