Study on the hydrolytic degradation behaviour of bictegravir by LC-PDA-Q/TOF-MS/MS NMR and in silico toxicity assessment.

Forced degradation studies provide rapid access to degradation products (DPs), where structural characterization and assessment of their potential toxicity are vital for pharmaceutical safety and regulatory compliance. As per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q1A R(2) guidelines, a forced degradation study of Bictegravir (BIC), a USFDA-approved drug for HIV wild type, in hydrolytic conditions (acid, base, and neutral) revealed the formation of six DPs in RP-HPLC (Reverse Phase- High-Performance Liquid Chromatography) gradient elution program using a C18 (4.6 × 250 mm, 5 µm) column. DP-1, 2, and 3 were characterized using liquid chromatography-tandem mass spectrometry (LC-MS/MS), whereas DP-4, 5, and 6 posed difficulties in characterization due to their isomeric nature. Using characteristic NOEs (Nuclear Overhauser Effect) from 2D ROESY NMR (Nuclear Magnetic Resonance) studies, we have elucidated diastereomeric DP-4/5 and isomeric DP-6/BIC configurational structures. Furthermore, in silico toxicity studies for the six degradation products were predicted for toxicity endpoints by employing DEREK, SARAH, and Pro Tox-II application tools. The DP-1 (methanamine) and DP-3 (carboxylic acid) resulting from acid-catalyzed hydrolysis, were predicted to have potential carcinogenic and mutagenic properties. These findings contribute significantly to our understanding of BIC's stability and safety profile in pharmaceutical development and underscore the rigorous characterization of stereoisomers by NMR that were further utilized for toxicity prediction.

Multicomponent Domino Reaction for Concise Access to 2-Amino-Substituted 1,3,4 Oxadiazoles via Smiles Rearrangement.

A multicomponent domino reaction has been developed for the preparation of N-substituted 2-amino-1,3,4-oxadiazoles directly from various hydrazides (32 examples). The formation of 2-amino-1,3,4-oxadiazole involves the Smiles rearrangement of thiazolidinone, which results in the formation of carbodiimide intermediate that concomitantly undergoes amide-imidic acid tautomerism followed by cyclization. The protocol developed has wide applicability and provides the desired 2-amino-1,3,4-oxadiazole in excellent yields. The GSD studies of NMR spectra of aliphatic substrates (4di, 4dh) revealed the formation of three products, whereas, in the case of allylic and benzylic substrates, thiazolidinones were obtained as the sole products. Furthermore, to elucidate the plausible mechanism, DFT studies were performed affirming carbodiimide as the crucial intermediate for the interconversion of thiazolidinone to oxadiazole.

Exo-trig selenocyclization of secondary allylic carboxamides using Woollins' reagent: en route to 2,5-disubstituted selenazolines.

We report microwave-assisted selenation and exo-trig cyclization of secondary allylic carboxamides using Woollins' reagent, a serendipitous finding observed during an attempt to synthesize N-allylbenzoselenoamide compounds. This resulted in the first reported synthesis of 2-aryl-5-methyl selenazolines. Twenty-one diversified selenazolines and three late-stage-functionalized drug molecules were synthesized in 42-93% and 25-52% yield, respectively, and these were evaluated further for their anti-proliferative activity.