Synthesis of Novel Benzothiazolo[3,2‐a]pyridimidin‐4‐ones with Potential Cytotoxic and Pro‐Apoptotic Potential

Abstract

The combination of cyclocondensation with palladium catalysed cross‐coupling reactions, afforded a variety of 8‐functionalized benzothiazolo[3,2‐a]pyridimidin‐4‐ones in good to excellent yields. The anti‐proliferative potential of the synthetic compounds was evaluated in human cervical adenocarcinoma cells (HeLa) and hamster normal fibroblasts (BHK‐21). Three of the test derivatives exhibited the strongest cytotoxicity in HeLa cells with the median inhibitory concentration (IC50) of 0.93, 1.55 and 1.84 μM, respectively. Moreover, their anti‐proliferative effect was three times less strong in normal fibroblasts, asserting their possible anti‐cancer potential.

Synthesis and Inhibitory Activity towards Monoamine Oxidase A and B of 8‐Functionalized 3‐Fluoro‐2‐methyl‐benzo[4,5]thiazolo[3,2‐a]pyrimidin‐4‐ones

“…The optimization was carried out for the synthesis of product 2 a , changing catalyst, solvent and base. Surprisingly, Pd 2 (dba) 3 as palladium source and Na 2 CO 3 as base gave only low to moderate yields which is in stark contrast to previously reported condition on a related non‐fluorinate starting material and highlights the electronic impact derived from fluorine substitution . However, the combination of Pd(OAc) 2 with K 3 PO 4 in a solvent mixture of 1,4‐dioxane and water gave the desired arylated product in high yield (Table ).…”

“…In the past, benzothiazolo[3,2 ‐ a ]pyrimidin ‐ 4 ‐ ones have been studied related to various pharmacological activities, like antibacterial‐ and antifungal properties and as inhibitors of HIV ‐ 1 . Very recently, we reported the synthesis of benzothiazolopyrimidones with cytotoxic and pro‐apoptotic activity . Nevertheless, despite their pharmacological relevance, only a few synthetic strategies for the synthesis and functionalization of benzothiazolo[3,2 ‐ a ]pyrimidin ‐ 4 ‐ ones are known to date .…”

“…Starting material 1 was synthesized, in analogy to a known procedure, by cyclocondensation of 2 ‐ amino ‐ 6 ‐ chloro‐benzothiazole with ethyl ‐ 2 ‐ fluoroacetoacetate (Scheme ). Afterwards, we surveyed its employement in various cross‐coupling reactions.…”

“…The second part of our study was related to the Buchwald‐Hartwig amination of substrate 1, owing to the role of the amino function in medicinal chemistry and pharmacology. As a starting point of our investigation, we used Pd 2 (dba) 3 and XPhos as catalyst and ligand, respectively, and toluene and NaO t Bu as solvent and base as these conditions proved to be effective for non‐fluorinated benzothiazolopyrimidones . Unfortunately, under these conditions, product 3a was obtained, albeit, in only 10% yield.…”

“…Finally, we studied Sonogashira reactions of 1 . Employing conditions previously developed by us for related molecules, the desired compounds 4 a‐d could be isolated in moderate to good yields (Table ).…”