Thiophene Ring-opening Reactions III: One-Pot Synthesis and Antitumor Activity of 1,3,4-Thiadiazoline-Benzothiazolo[3,2- b]pyridazine Hybrids†

Abstract

Introduction: The preparation of model 6-chloro-5-nitrothieno[2,3-c]pyridazines incorporating (2'-halo-5'-nitrophenyl) entity is described. Interaction of these substrates with N'-(aryl)benzothiohydrazides, in the presence of triethylamine, followed a formal [4+1] annulation, furnishing the respective 1,3,4-thiadiazoline-benzothiazolo [3,2-b]pyridazine hybrids directly. This one-pot synthesis implies thiophene ring-opening and two consecutive intramolecular cyclizations. The structures of the synthesized new hybrids are supported by MS, NMR, and IR spectral data and further confirmed by single-crystal X-ray diffraction. These hybrids exhibit antiproliferative activity with notable selectivity against solid tumor cell lines (IC₅₀: 4-18 μM).

Aims: This study aimed at exploring the scope and applicability of thiophene ring-opening reaction towards the synthesis of new thiadiazoline-[fused]tricyclic conjugates.

Background: α-Chloro-β-nitrothienopyridazine underwent ring-opening upon reacting with N'-(aryl)benzothiohydrazides generating 1,3,4-thiadiazoline-benzothiazolo[3,2-b]pyridazines.

Objective: This new thiophene ring-opening reaction is applied to the one-pot synthesis of thiadiazoline-benzothiazolo[3,2-b]pyridazine couples.

Method: A direct interaction of α-chloro-β-nitrothienopyridazine with N'-(aryl)benzothio-hydrazide at room temperature for 1-2 h occurred.

Result: a-Chloro-β-nitrothieno[2,3-c]pyridazines are suitable substrates for the facile synthesis of thiadiazoline-benzothiazolo[3,2-b]pyridazine hybrids.

Conclusion: This novel ring-opening reaction proceeds via formal [4+1] annulation and provides a versatile approach to various conjugated and/or fused five-membered heterocycles.

Keywords: 1,3,4-thiadiazoline-[fused]tricyclic hybrids; 6-chloro-5-nitrothieno[2,3-c]pyridazines; Antitumor activity; N'-(Aryl)benzothiohydrazides; formal [4+1] annulation; heterocyclic rings.