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Exploration of the structure-activity relationship of 1,2,4-oxadiazole antibiotics.

ABSTRACT: We have recently disclosed the discovery of the class of 1,2,4-oxadiazole antibiotics, which emerged from in silico docking and scoring efforts. This class of antibacterials exhibits Gram-positive activity, particularly against Staphylococcus aureus. We define the structure-activity relationship (SAR) of this class of antibiotics with the synthesis and evaluation of a series of 59 derivatives with variations in the C ring or C and D rings. A total of 17 compounds showed activity against S. aureus. Four derivatives were evaluated against a panel of 16 Gram-positive strains, inclusive of several methicillin-resistant S. aureus strains. These compounds are broadly active against Gram-positive bacteria.

SUBMITTER: Ding D

PROVIDER: S-EPMC4607640 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Exploration of the structure-activity relationship of 1,2,4-oxadiazole antibiotics.

Ding Derong D Boudreau Marc A MA Leemans Erika E Spink Edward E Yamaguchi Takao T Testero Sebastian A SA O'Daniel Peter I PI Lastochkin Elena E Chang Mayland M Mobashery Shahriar S

Bioorganic & medicinal chemistry letters 20150618 21

We have recently disclosed the discovery of the class of 1,2,4-oxadiazole antibiotics, which emerged from in silico docking and scoring efforts. This class of antibacterials exhibits Gram-positive activity, particularly against Staphylococcus aureus. We define the structure-activity relationship (SAR) of this class of antibiotics with the synthesis and evaluation of a series of 59 derivatives with variations in the C ring or C and D rings. A total of 17 compounds showed activity against S. aureu ...[more]

PMID: 26144346

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Structure-activity relationship for the oxadiazole class of antibiotics.

Project description:The structure-activity relationship (SAR) for the newly discovered oxadiazole class of antibiotics is described with evaluation of 120 derivatives of the lead structure. This class of antibiotics was discovered by in silico docking and scoring against the crystal structure of a penicillin-binding protein. They impair cell-wall biosynthesis and exhibit activities against the Gram-positive bacterium Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant and linezolid-resistant S. aureus. 5-(1H-Indol-5-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole (antibiotic 75b) was efficacious in a mouse model of MRSA infection, exhibiting a long half-life, a high volume of distribution, and low clearance. This antibiotic is bactericidal and is orally bioavailable in mice. This class of antibiotics holds great promise in recourse against infections by MRSA.

| S-EPMC6863074 | biostudies-literature

Structure-Activity Relationship for the Oxadiazole Class of Antibacterials.

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| S-EPMC7073871 | biostudies-literature

Design, synthesis, and biological activity of novel 1,2,4-oxadiazole derivatives.

Project description:BackgroundPlant diseases seriously threaten food security, it is urgent to discover efficient and low-risk chemical pesticides. 1,2,4-Oxadiazole derivatives exhibit broad spectrum of agricultural biological activities. For discovering novel molecules with excellent agricultural activities, novel 1,2,4-oxadiazole derivatives were synthesized and evaluated for their agricultural activities.ResultBioassays results showed that the title compounds exhibited moderate nematocidal activity against Meloidogyne incognita and anti-fungal activity to Rhizoctonia solani. It's worth noting that compounds 5m, 5r, 5u, 5v, 5x and 5y showed strong antibacterial effects on Xanthomonas oryzae pv. oryzae (Xoo), with EC50 values of 36.25, 24.14, 28.82, 19.44, 25.37 and 28.52 ?g/mL, respectively, superior to bismerthiazol (BMT, EC50?=?77.46 ?g/mL) and thiodiazole copper (TDC, EC50?=?99.31 ?g/mL). Compounds 5p, 5u and 5v exhibited excellent antibacterial ability against Xanthomonas oryzae pv. oryzicola (Xoc), with EC50 values of 31.40, 19.04 and 21.78 ?g/mL, respectively, better than that of BMT (EC50?=?68.50 ?g/mL) and TDC (EC50?=?91.05 ?g/mL). In addition, compound 5v exerted moderate antibacterial effects on rice bacterial leaf blight.ConclusionsTwenty-six novel 1,2,4-oxadiazole derivatives were obtained and their biological activities were evaluated. Compound 5u and 5v exhibited excellent antibacterial activity Xoo and Xoc. These results indicated that 1,2,4-oxadiazole derivatives containing a trifluoromethyl pyridine moiety could be as potential alternative templates for discovering novel antibacterial agents.

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Structure-Based Bioisosterism Design, Synthesis, Biological Activity and Toxicity of 1,2,4-Oxadiazole Substituted Benzamides Analogues Containing Pyrazole Rings.

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| S-EPMC9330712 | biostudies-literature

Synthesis and Biological Activity of Benzamides Substituted with Pyridine-Linked 1,2,4-Oxadiazole.

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| S-EPMC7435590 | biostudies-literature

Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit.

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| S-EPMC6983020 | biostudies-literature

Electrocyclic Ring-Opening of 1,2,4-Oxadiazole[4,5-<i>a</i>]piridinium Chloride: a New Route to 1,2,4-Oxadiazole Dienamino Compounds.

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| S-EPMC6739692 | biostudies-literature

New 1,2,4-oxadiazole derivatives with positive mGlu4 receptor modulation activity and antipsychotic-like properties.

Project description:Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu4 receptor positive allosteric modulatory activity (EC50 = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu1, mGlu2 and mGlu5 receptors, but modulated mGlu7 and mGlu8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu4 PAM ADX88178.

| S-EPMC8667925 | biostudies-literature

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| S-EPMC8836147 | biostudies-literature

Design, Synthesis, and Biological Activity of Novel Chalcone Derivatives Containing an 1,2,4-Oxadiazole Moiety

Project description:To discover a lead compound for agricultural use, 34 novel chalcone derivatives containing an 1,2,4-oxadiazole moiety were designed and synthesized. Their nematocidal activities against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus dipsaci and their antiviral activities against tobacco mosaic virus (TMV), pepper mild mottle virus (PMMoV), and tomato spotted wilt virus (TSWV) were evaluated. Biological assay results indicate that compounds A13 and A14 showed good nematocidal activities against B. xylophilus, A. besseyi, and D. dipsaci, with LC50 values of 35.5, 44.7, and 30.2 μg/ml and 31.8, 47.4, and 36.5 μg/ml, respectively, which are better than tioxazafen, fosthiazate, and abamectin. Furthermore, compound A16 demonstrated excellent protective activity against TMV, PMMoV, and TSWV, with EC50 values of 210.4, 156.2, and 178.2 μg/ml, respectively, which are superior to ningnanmycin (242.6, 218.4, and 180.5 μg/ml).

| S-EPMC9354253 | biostudies-literature

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