Trifluoromethylpyridine 1,3,4-Oxadiazole Derivatives: Emerging Scaffolds as Bacterial Agents.
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ABSTRACT:
SUBMITTER: Yu G
PROVIDER: S-EPMC8613808 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this paper, we aimed to exploit and combine in the same molecule the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives, by using two synthesis pathways. For the first route, the following steps have been followed: (i) (RS)-2-(6-chloro-9H-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (RS)-2-(6-chloro-9H-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to N-[(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoil]-N'-R-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-(1,3,4-oxadiazol-2-yl)ethane derivatives. In the second synthesis pathway, new 1,3,4-oxadiazole ring compounds were obtained starting from carprofen which was reacted with isoniazid, in the presence of phosphorus oxychloride to form (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, 1H-NMR and 13C-NMR, screened for their drug-like properties and evaluated for in vitro cytotoxicity and antimicrobial activity. The obtained compounds exhibited a good antimicrobial activity, some of the compounds being particularly active on E. coli, while others on C. albicans. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the P. aeruginosa biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 μg/mL, the tested compounds do not induce cytotoxicity and do not alter the mammalian cell cycle. The new synthesized compounds show good drug-like properties. The ADME-Tox profiles indicate a good oral absorption and average permeability through the blood brain barrier. However, further research is needed to reduce the predicted mutagenic potential and the hepatotoxicity.
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Project description:A library of 1,2,3-triazole-incorporated thymol-1,3,4-oxadiazole derivatives (6-18) hasbeen synthesized and tested for anticancer and antimicrobial activities. Compounds 7, 8, 9, 10, and 11 exhibited significant antiproliferative activity. Among these active derivatives, compound 2-(4-((5-((2-isopropyl-5-methylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)phenol (9) was the best compound against all three tested cell lines, MCF-7 (IC50 1.1 μM), HCT-116 (IC50 2.6 μM), and HepG2 (IC50 1.4 μM). Compound 9 was found to be better than the standard drugs, doxorubicin and 5-fluorouracil. These compounds showed anticancer activity through thymidylate synthase inhibition as they displayed significant TS inhibitory activity with IC50 in the range 1.95-4.24 μM, whereas the standard drug, Pemetrexed, showed IC50 7.26 μM. The antimicrobial results showed that some of the compounds (6, 7, 9, 16, and 17) exhibited good inhibition on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The molecular docking and simulation studies supported the anticancer and antimicrobial data. It can be concluded that the synthesized 1,2,3-triazole tethered thymol-1,3,4-oxadiazole conjugates have both antiproliferative and antimicrobial potential.
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Project description:A series of novel 2,5-disubstituted-1,3,4-oxadiazole derivatives were synthesized and screened for their antimicrobial and antioxidant activities. The assay indicated that compounds 3c, 3d, and 3i exhibited comparable antibacterial and antioxidant activity with first-line drugs. The structure activity relationship and molecular docking study of the synthesized compounds are also reported.
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Project description:Rice bacterial leaf blight and leaf streak are two important bacterial diseases of rice, which can result in yield loss. Currently, effective antimicrobials for rice bacterial diseases are still lacking. Thus, to develop highly effective and low-risk bactericides, 31 novel 1,3,4-oxadiazole derivatives containing a cinnamic acid moiety were designed and synthesized. Bioassay results demonstrated that all compounds exhibited good antibacterial activities in vitro. Significantly, compounds 5r and 5t showed excellent antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and X. oryzae pv. oryzicola (Xoc), with the 50% effective concentration (EC50) values of 0.58 and 0.34, and 0.44 and 0.20 μg/mL, respectively. These compounds were much better than thiodiazole copper (123.10 and 161.52 μg/mL) and bismerthiazol (85.66 and 110.96 μg/mL). Moreover, compound 5t had better protective and curative activities against rice bacterial leaf blight and leaf streak than thiodiazole copper and bismerthiazol in vivo. Simultaneously, the in vivo efficacy of the compounds was demonstrated by real-time quantitative PCR to quantify bacterial titers. In addition, a three-dimensional quantitative structure⁻activity relationship model was created and presented good predictive ability. This work provides support for 1,3,4-oxadiazole derivatives containing a cinnamic acid moiety as a potential new bactericide for rice bacterial diseases.
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Project description:We report the synthesis and biological assessment of 1,3,4-oxadiazole substituted 24 derivatives as novel, potential antibacterial agents. The structures of the newly synthesized derivatives were established by the combined practice of UV, IR, (1)H NMR, (13)C NMR, and mass spectrometry. Further these synthesized derivatives were subjected to antibacterial activity against all the selected microbial strains in comparison with amoxicillin and cefixime. The antibacterial activity of synthesized derivatives was correlated with their physicochemical and structural properties by QSAR analysis using computer assisted multiple regression analysis and four sound predictive models were generated with good R(2), R(adj)(2), and Fischer statistic. The derivatives with potent antibacterial activity were subjected to molecular docking studies to investigate the interactions between the active derivatives and amino acid residues existing in the active site of peptide deformylase to assess their antibacterial potential as peptide deformylase inhibitor.
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Project description:A new series of 1,3,4-oxadiazoles derivatives was synthesized, characterized, and evaluated for their in vitro and in vivo anti-thrombotic activity. Compounds (3a?3i) exhibited significant clot lysis with respect to reference drug streptokinase (30,000 IU), and enhanced clotting time (CT) values (130?342 s) than heparin (110 s). High affinity towards 1NFY with greater docking score was observed for the compounds (3a, 3i, 3e, 3d, and 3h) than the control ligand RPR200095. In addition, impressive inhibitory potential against factor Xa (F-Xa) was observed with higher docking scores (5612?6270) with Atomic Contact Energy (ACE) values (-189.68 to -352.28 kcal/mol) than the control ligand RPR200095 (Docking score 5192; ACE -197.81 kcal/mol). In vitro, in vivo, and in silico results proposed that these newly synthesized compounds might be used as anticoagulant agents.
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Project description:A series of novel ?-carboline 1,3,4-oxadiazole derivatives were designed and synthesized, and the in vitro cytotoxic activity against Sf9 cells and growth inhibitory activity against Spodoptera litura were evaluated. Bioassay results showed that most of these compounds exhibited excellent in vitro cytotoxic activity. Especially, compound 37 displayed the best efficacy in vitro (IC50 = 3.93 ?M), and was five-fold more potent than camptothecin (CPT) (IC50 = 18.95 ?M). Moreover, compounds 5 and 37 could induce cell apoptosis and cell cycle arrest and stimulate Sf-caspase-1 activation in Sf9 cells. In vivo bioassay also demonstrated that compounds 5 and 37 could significantly inhibit larvae growth of S. litura with decreasing the weight of larvae and pupae. Based on these bioassay results, compounds 5 and 37 emerged as lead compounds for the development of potential insect growth inhibitions.
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Project description:BackgroundPant diseases in agriculture are extremely difficult to control, which bring about for billions of dollars in economic losses worldwide each year; Nicotinamide derivatives has attracted more and more attention in the field of pesticide due to their broad bioactivities. In an effort to discover new molecules with good antifungal activity, a series of nicotinamide derivatives containing 1,3,4-oxadiazole were synthesized and bio-assayed.ResultsBioassays demonstrated that some of the title compounds exhibited favorable antifungal activities against Gibberella zeae, Fusarium oxysporum, and Cytospora mandshurica. compounds 7b, 7c, 8, 9a, 9b, and 9c displayed 46.4%, 39.6%, 53.0%, 43.2%, 58.3%, 45.6% activities against G. Zeae, respectively; the activities of compounds 7a, 7b, 8, 9a, 9b, and 9c against F. oxysporum were 55.2%, 51.1%, 58.9%, 63.2%, 53.3%, and 47.6%, respectively; whereas inhibitory rates of compounds 7a, 7b, 7c, 8, 9a, 9b, and 9c on C. mandshurica were 53.1%, 49.9%, 44.9%, 52.8%, 59.8%, 54.5%, and 49.3%, respectively.ConclusionA series of the novel nicotinamide derivatives containing 1,3,4-oxadiazole were synthesized and bio-assayed. The results of antifungal tests revealed that the synthesized nicotinamide derivatives possessed weakly to moderately antifungal activities against G. zeae, F. oxysporum, and C. mandshurica. Most of the synthesized compounds exhibited similar activities as (or higher than) these of hymexozol on their corresponding fungus, and compounds 7a, 8, 9a, and 9b showed considerable prospects for further optimization. Primary structure-activity relationships revealed that the introduction of the groups of 4-chloro-6-methyl on benzene, the hydrazone group containing N,N-dimethylamino, and acetyl at -NH2 could enhance the antifungal activity.
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Project description:Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases.
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