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Clinical Pharmacokinetics Apr 2022Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The... (Review)
Review
Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The aim of the review was to summarize and critically review the key pharmacokinetic and pharmacodynamic aspects of tedizolid. Tedizolid displays linear pharmacokinetics with good tissue penetration. In in vitro susceptibility studies, tedizolid exhibits activity against the majority of Gram-positive bacteria (minimal inhibitory concentration [MIC] of ≤ 0.5 mg/L), is four-fold more potent than linezolid, and has the potential to treat pathogens being less susceptible to linezolid. Area under the unbound concentration-time curve (fAUC) related to MIC (fAUC/MIC) was best correlated with efficacy. In neutropenic mice, fAUC/MIC of ~ 50 and ~ 20 induced bacteriostasis in thigh and pulmonary infection models, respectively, at 24 h. The presence of granulocytes augmented its antibacterial effect. Hence, tedizolid is currently not recommended for immunocompromised patients. Clinical investigations with daily doses of 200 mg for 6 days showed non-inferiority to twice-daily dosing of linezolid 600 mg for 10 days in patients with acute bacterial skin and skin-structure infections. In addition to its use in skin and skin-structure infections, the high pulmonary penetration makes it an attractive option for respiratory infections including Mycobacterium tuberculosis. Resistance against tedizolid is rare yet effective antimicrobial surveillance and defining pharmacokinetic/pharmacodynamic targets for resistance suppression are needed to guide dosing strategies to suppress resistance development.
Topics: Animals; Anti-Bacterial Agents; Humans; Mice; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Oxazolidinones; Tetrazoles
PubMed: 35128625
DOI: 10.1007/s40262-021-01099-7 -
Marine Drugs Nov 2010Thiazoles, oxazole and their corresponding reduced derivatives, thiazolines and oxazolines, are found in marine sources exhibiting significant biological activities. The... (Review)
Review
Thiazoles, oxazole and their corresponding reduced derivatives, thiazolines and oxazolines, are found in marine sources exhibiting significant biological activities. The isolation, synthetic, and biological studies of these natural products, covering literature from January 2007 to June 2010, are summarized.
Topics: Alkaloids; Animals; Biological Products; Drug Design; Drug Discovery; Humans; Oxazoles; Thiazoles
PubMed: 21139843
DOI: 10.3390/md8112755 -
Biomedicine & Pharmacotherapy =... Jun 2021Thiazole and oxazole are compounds with a heterocyclic nucleus that have attracted the attention of medicinal chemistry due to the great variety of biological activities... (Review)
Review
Thiazole and oxazole are compounds with a heterocyclic nucleus that have attracted the attention of medicinal chemistry due to the great variety of biological activities that they enable. In recent years, their study has increased, finding a wide range of biological activities, including antifungal, antiparasitic, anti-inflammatory, and anticancer activities. This systematic review provides evidence from the literature on the antiproliferative and antitumor activities of thiazole and oxazole and their derivatives from 2014 to April 2020. Three bibliographical databases were consulted (PubMed, Web of Science, and Scopus), and a total of 32 studies were included in this paper based on our eligibility criteria. The analysis of the activity-structure relationship allows us to conclude that most of the promising compounds identified contained thiazole nuclei or derivatives.
Topics: A549 Cells; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antifungal Agents; Cell Proliferation; HeLa Cells; Hep G2 Cells; Humans; Oxazoles; Structure-Activity Relationship; Thiazoles
PubMed: 33765586
DOI: 10.1016/j.biopha.2021.111495 -
International Journal of Molecular... Aug 2022Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and...
Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and novel approaches to discover novel drugs are urgently needed. Herein, 2D- and 4D-quantitative structure-activity relationship (QSAR) models were developed for a series of oxazole and oxadiazole derivatives that are active against , the causative agent of visceral leishmaniasis. A clustering strategy based on structural similarity was applied with molecular fingerprints to divide the complete set of compounds into two groups. Hierarchical clustering was followed by the development of 2D- ( = 0.90, pred = 0.82) and 4D-QSAR models ( = 0.80, pred = 0.64), which showed improved statistical robustness and predictive ability.
Topics: Antiprotozoal Agents; Cluster Analysis; Humans; Leishmaniasis, Visceral; Oxadiazoles; Oxazoles; Quantitative Structure-Activity Relationship
PubMed: 36012163
DOI: 10.3390/ijms23168898 -
ACS Chemical Neuroscience Oct 2018Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been... (Review)
Review
Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as "designer drugs" in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4'-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this Review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogues. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This Review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e., deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency, or the identity of the active ingredients remains obscure to NPS users.
Topics: Aminorex; Central Nervous System Stimulants; Designer Drugs; History, 20th Century; History, 21st Century; Humans
PubMed: 30269490
DOI: 10.1021/acschemneuro.8b00415 -
The Journal of Antimicrobial... Mar 2022Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably...
Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.
Topics: Antitubercular Agents; Diarylquinolines; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant
PubMed: 35089314
DOI: 10.1093/jac/dkab505 -
Marine Drugs Apr 2020Oxazole-containing peptides are mostly of marine origin and they form an intriguing family with a broad range of biological activities. Here we classify these peptides... (Review)
Review
Oxazole-containing peptides are mostly of marine origin and they form an intriguing family with a broad range of biological activities. Here we classify these peptides on the basis of their chemical structure and discuss a number of representatives of each class that reflect the extraordinary potential of this family as a source of new drugs.
Topics: Animals; Aquatic Organisms; Drugs, Investigational; Oxazoles
PubMed: 32290087
DOI: 10.3390/md18040203 -
Angewandte Chemie (International Ed. in... Jun 2016Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades... (Review)
Review
Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last-resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled "Combat drug resistance: no action today means no cure tomorrow" triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Drug Design; Drug Resistance, Multiple, Bacterial; Macrolides; Molecular Dynamics Simulation; Organophosphates; Oxazoles; Oxazolidinones; Structure-Activity Relationship
PubMed: 27000559
DOI: 10.1002/anie.201506818 -
Biosynthesis Gene Cluster and Oxazole Ring Formation Enzyme for Inthomycins in sp. Strain SYP-A7193.Applied and Environmental Microbiology Oct 2020Inthomycins belong to a growing family of oxazole-containing polyketides and exhibit a broad spectrum of anti-oomycete and herbicidal activities. In this study, we...
Inthomycins belong to a growing family of oxazole-containing polyketides and exhibit a broad spectrum of anti-oomycete and herbicidal activities. In this study, we purified inthomycins A and B from the metabolites of sp. strain SYP-A7193 and determined their chemical structures. Genome sequencing, comparative genomic analysis, and gene disruption of sp. SYP-A7193 showed that the inthomycin biosynthetic gene cluster () belonged to the hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) system. Functional domain comparison and disruption/complementation experiments of resulted in the complete loss of inthomycins A and B and the subsequent restoration of their production, confirming that encodes a discrete acyltransferase (AT), and hence, was considered to belong to the -AT type I PKS system. Moreover, the disruption/complementation experiments of also resulted in the loss and restoration of inthomycin A and B formation. Further gene cloning, expression, purification, and activity verification of revealed that Itm15 is a cyclodehydratase that catalyzes a straight-chain dehydration reaction to form an oxazole ring for the biosynthesis of inthomycins A and B. Thus, we discovered a novel enzyme that catalyzes oxazole ring formation and elucidated the complete biosynthetic pathway of inthomycins. species produce numerous secondary metabolites with diverse structures and pharmacological activities that are beneficial for human health and have several applications in agriculture. In this study, hybrid nonribosomal peptide synthetase/polyketide synthase metabolites inthomycins A and B were isolated from after fermenting sp. SYP-A7193. Genome sequencing, gene disruption, gene complementation, heterologous expression, and activity assay revealed that the biosynthesis gene assembly line of inthomycins A and B was a 95.3-kb -AT type I PKS system in the strain SYP-A7193. More importantly, Itm15, a cyclodehydratase, was identified to be an oxazole ring formation enzyme required for the biosynthesis of inthomycins A and B; it is significant to discover this catalyzation reaction in the PKS/NRPS system in the field of microbiology. Our findings could provide further insights into the diversity of -AT type I PKS systems and the mechanism of oxazole cyclization involved in the biosynthesis of natural products.
Topics: Fatty Acids, Unsaturated; Genes, Bacterial; Multigene Family; Oxazoles; Streptomyces
PubMed: 32801183
DOI: 10.1128/AEM.01388-20 -
Canadian Family Physician Medecin de... Jun 1999*Zolmitriptan (Zomig) is an antimigraine drug similar to sumatriptan.*The clinical file mainly comprises placebo-controlled, dose-finding studies recommending an optimal...
*Zolmitriptan (Zomig) is an antimigraine drug similar to sumatriptan.*The clinical file mainly comprises placebo-controlled, dose-finding studies recommending an optimal oral dose of 2.5 mg.*Zolmitriptan has been compared with sumatriptan in a trial that showed no difference in efficacy. In particular, the recurrence rate of headache after initial relief was not lower on zolmitriptan than on sumatriptan.*The safety profile of zolmitriptan is similar to that of sumatriptan. The contraindications relating to a history of cardiovascular disease must be respected because of the vasoconstrictive effect of the drug.*Zolmitriptan has the same drug interactions as sumatriptan. Zolmitriptan should not be used during migraine attacks by patients using propranolol.
Topics: Drug Interactions; Humans; Migraine Disorders; Oxazoles; Oxazolidinones; Serotonin Receptor Agonists; Sumatriptan; Tryptamines
PubMed: 10386213
DOI: No ID Found