Reaction of irbesartan with nitrous acid produces irbesartan oxime derivatives, rather than N-nitrosoirbesartan

In October 2021, an India-based pharmaceutical company withdrew a number of batches of irbesartan and irbesartan hydrochlorothiazide finished products from the US market, due to the presence of unacceptable level of the “probably carcinogenic” nitrosamine “N-nitrosoirbesartan”. Nevertheless, there is no revealing of the exact structure of this so called “N-nitrosoirbesartan”. In the current study, we performed a set of 10 reactions of irbesartan with nitrous acid under various conditions and found no trace of this “N-nitrosoirbesartan” by a sensitive and accurate LC-MS method with limit of detection (LOD) of 30 ppb. With the use of LC-PDA/UV-high resolution MSn as well as 1D/2D NMR, the reaction products formed are found to be the two isomeric oxime derivatives of irbesartan, with the Z-isomer as the predominant product. Furthermore, no trace of this “N-nitrosoirbesartan” can be detected in representative commercial batches of irbesartan. Despite of the fact that in silico evaluation suggests that the two irbesartan oximes may be controlled as regular impurities, analysis of representative irbesartan commercial batches by the LC-MS method indicates that the oximes are not detected (LOD: 30 ppb).

SYNTHESIS AND ANTIMICROBIAL EVALUATION OF SOME NEW BENZTHIAZOLE OXIME ETHER DERIVATIVES

Some new oxime ether derivatives containing benzthiazole heterocyclic nuclei are synthesized. The reaction of 2-mercapto benzthiazole with α-halo ketones followed by reaction with hydroxylamine gave oxime derivatives which on reaction with alkyl halides viz. ethyl chloride, n-propyl chloride, and n-butyl chloride in absolute ethanol afforded the target compounds 4a-l. The structure of all the synthesized compounds was confirmed by spectroscopic methods like mass and NMR. All compounds after structural confirmation were tested for biological activities.

Synthesis, In Silico Studies, and Evaluation of Syn and Anti Isomers of N-Substituted Indole-3-carbaldehyde Oxime Derivatives as Urease Inhibitors against Helicobacter pylori

Gastrointestinal tract infection caused by Helicobacter pylori is a common virulent disease found worldwide, and the infection rate is much higher in developing countries than in developed ones. In the pathogenesis of H. pylori in the gastrointestinal tract, the secretion of the urease enzyme plays a major role. Therefore, inhibition of urease is a better approach against H. pylori infection. In the present study, a series of syn and anti isomers of N-substituted indole-3-carbaldehyde oxime derivatives was synthesized via Schiff base reaction of appropriate carbaldehyde derivatives with hydroxylamine hydrochloride. The in vitro urease inhibitory activities of those derivatives were evaluated against that of Macrotyloma uniflorum urease using the modified Berthelot reaction. Out of the tested compounds, compound 8 (IC50 = 0.0516 ± 0.0035 mM) and compound 9 (IC50 = 0.0345 ± 0.0008 mM) were identified as the derivatives with potent urease inhibitory activity with compared to thiourea (IC50 = 0.2387 ± 0.0048 mM). Additionally, in silico studies for all oxime compounds were performed to investigate the binding interactions with the active site of the urease enzyme compared to thiourea. Furthermore, the drug-likeness of the synthesized oxime compounds was also predicted.

New Approaches for the Synthesis of Heterocyclic Compounds Derived from Cyclohexan-1,3-dione with Anti-proliferative Activities

In the present work a series of heterocyclization reactions were adopted using cyclohexan-1,3-dione through its reaction with either furan-2-carbaldehyde or thiophene-2-carbaldehyde to give the corresponding ylidene derivatives 3a,b. The latter compounds underwent heterocyclization reactions to give thiophene and pyran derivatives 5a–d and 6a–d, respectively. Moreover, compounds 3a,b reacted with elemental sulfur and phenyl isothiocyanate to give the fused thiazole derivatives 8a,b. In addition, the reaction with either of hydrazine hydrate or phenylhydrazine has given the 4-hydrazono-4,5,6,7-tetrahydro-2H-indazole derivatives 10a–d, respectively. Similarly, the reaction of either 3a or 3b with hydroxylamine hydrochloride gave the 6,7-dihydrobenzo[c]isoxazol-4(5H)-one oxime derivatives 12a and 12b, respectively. Other fused heterocyclic compounds were produced and their structures were elucidated. Evaluation of the synthesized compounds against selected cancer cell lines was performed. The most active compounds were further evaluated against tyrosine kinases and Pim-1 kinase inhibitions.

Photocatalytic cross-couplings via the cleavage of N-O bonds

N-(Acyloxy)phthalimide and oxime derivatives containing N-O bonds are important chemicals and synthetic intermediates, and visible-light photoredox reductions of the N-O bonds provide the carbon- or nitrogen-centered radicals for N-(acyloxy)phthalimide derivatives...