Nitro-substituted 1,3-benzothiazinones (nitro-BTZs) are mechanism-based covalent inhibitors of Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose-2′-oxidase (DprE1) with strong antimycobacterial properties. We prepared a number of oxidized and reduced forms of nitro-BTZs to probe the mechanism of inactivation of the enzyme and to identify opportunities for further chemistry. The kinetics of inactivation of DprE1 was examined using an enzymatic assay that monitored reaction progress up to 100 min, permitting compound ranking according to kinact/Ki values. The side-chain at the 2-position and heteroatom identity at the 1-position of the BTZs were found to be important for inhibitory activity. We obtained crystal structures with several compounds covalently bound. The data suggest that steps upstream from the covalent end-points are likely the key determinants of potency and reactivity. The results of protein mass spectrometry using a 7-chloro-nitro-BTZ suggest that nucleophilic reactions at the 7-position do not operate and support a previously proposed mechanism in which BTZ activation by a reduced flavin intermediate is required. Unexpectedly, a hydroxylamino-BTZ showed time-dependent inhibition and mass spectrometry corroborated that this hydroxylamino-BTZ is a mechanism-based suicide inhibitor of DprE1. With this BTZ derivative, we propose a new covalent mechanism of inhibition of DprE1 that takes advantage of the oxidation cycle of the enzyme.
8‐Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence‐based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high‐throughput macrophage infection assay.
Objective: To compare 18 F-PSMA-1007 and 18 F-fluorocholine PET/CT for localization of prostate cancer (PCa) biochemical recurrence.
Methods:This prospective, open-label, randomized, cross-over, multicenter study, included prostate cancer patients with prior definitive therapy and suspicion of PCa recurrence. All men underwent both 18 F-PSMA-1007 and 18 F-fluorocholine PET/CT (102 received 18 F-PSMA-1007 first and 88 received 18 F-fluorocholine PET/CT first). All images were assessed independently by three readers blinded to all clinical information using a 3-point qualitative scale (0-no-recurrence; 1-undetermined; 2-recurrence). Patients were followed for approximately 6 months. An independent panel with a urologist, radiologist, and nuclear physician reviewed all clinical data, including imaging and response to therapy but blinded to PET/CT information, and acting in consensus, determined a patient-based and region-based composite standard of truth for PCa lesions. The "correct detection rate" of PCa lesions on a patient-basis for each radiopharmaceutical was compared for the three readers individually and for the average reader. Secondary objectives included determining if PET/CT findings impact diagnostic thinking (impact of a test result on post-test versus pre-test probability of a correct diagnosis), therapeutic decision making (description and quantification of impact of diagnostic information gained with both radiopharmaceuticals on patient management), and adequacy of management changes.Results: A total of 190 patients were included. The primary endpoint was met. Overall correct detection rate of 18 F-PSMA-1007 was 0.82 vs 0.65 for 18 F-fluorocholine (p<0.0001) when considering undetermined findings as positive for malignancy, and 0.77 vs 0.57 respectively (p<0.0001) when considering undetermined findings as negative for malignancy. A change in diagnostic thinking due to PET/CT was reported in 149 patients among whom 18 F-PSMA-1007 contributed more than 18 F-fluorocholine in 93. In 122 patients, PET/CT led to an adequate 4 diagnosis which benefited the patient, among whom 18 F-PSMA-1007 contributed more than 18 Ffluorocholine in 88 patients.Conclusions: 18 F-PSMA-1007 PET/CT is superior to 18 F-fluorocholine PET/CT in localization of PCa recurrence. Decision making was more adequate when based on 18 F-PSMA-1007 PET/CT results.
1,3-Benzothiazin-4-ones (BTZs) are a promising new class of anti-tuberculosis drug candidates, some of which have reached clinical trials. The title compound, the benzamide derivative [2-chloro-3-nitro-5-(trifluoromethyl)phenyl](piperidin-1-yl)methanone, C13H12ClF3N2O3, occurs as a side product as a result of competitive reaction pathways in the nucleophilic attack during the synthesis of the BTZ 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-1,3-benzothiazin-4-one, following the original synthetic route, whereby the corresponding benzoyl isothiocyanate is reacted with piperidine as secondary amine. In the title compound, the nitro group and the nearly planar amide group are significantly twisted out of the plane of the benzene ring. The piperidine ring adopts a chair conformation. The trifluoromethyl group exhibits slight rotational disorder with a refined ratio of occupancies of 0.972 (2):0.028 (2). There is structural evidence for intermolecular weak C—H...O hydrogen bonds.
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