Serendipitous N,S-difunctionalization of triazoles with trifluoromethyl-ß-diketones: access to regioisomeric 1-trifluoroacetyl-3-aryl-5-(2-oxo-2-arylethylthio)-1,2,4-triazoles as DNA-groove binders.

In the present research work, a serendipitous regioselective synthesis of DNA targeting agents, 1-trifluoroacetyl-3-aryl-5-(2-oxo-2-arylethylthio)-1,2,4-triazoles, has been achieved through the one-pot cascade reaction of 3-mercapto[1,2,4]triazoles with trifluoromethyl-ß-diktetones in presence of NBS instead of the cyclized thiazolo[3,2-b][1,2,4]triazole. The present protocol offered a unique approach for functionalizing both N-acylation and S-alkylation in a concerted fashion. The structures of the regioisomeric products were thoroughly characterized by heteronuclear 2D NMR experiments. Facile scalability and excellent atom economy through easily available starting reactants are the notable features of the present sustainable protocol. Targeting tumor cell DNA with minor groove-binding small molecules has proven highly effective in the recent past, drawing significant attention for combating tumor-related afflictions. In this context, the synthesized analogs were primarily screened for their ability to bind with the DNA duplex d(CGCGAATTCGCG)2 using molecular modeling tools. Additionally, the most promising compound 14m was deployed as a probe for DNA sensing and interaction mechanisms with calf thymus (ct)DNA through various spectral techniques at a physiologic temperature of 37 °C. It has been found that the compound demonstrated a strong binding affinity (Kb = 1 × 105 M-1) with double-helical DNA, particularly within the minor groove, resulting in the formation of a stable complex through static quenching (Kq = 5.86 ± 0.11 × 1012 M-1 s-1). The fluorescent displacement assay confirmed that the quencher binds to the minor groove of ctDNA, further supported by circular dichroism and viscosity studies.

An expeditious on-water regioselective synthesis of novel arylidene-hydrazinyl-thiazoles as DNA targeting agents.

A series of twenty novel (E)-arylidene-hydrazinyl-thiazole derivatives has been synthesized employing α-bromo-ß-diketones, thiosemicarbazide, and aromatic/heteroaromatic aldehydes with a simple and facile one-pot multicomponent reaction passageway. This organic transformation proceeds efficiently in aqueous media and demonstrated a large functional group tolerance. The structures and stereochemistry of the regioisomeric product were rigorously characterized using heteronuclear 2D NMR experiments. The binding potential of the synthesized analogs with B-DNA dodecamer d(CGCGAATTCGCG)2 was primarily screened using molecular modeling tools and further, mechanistic investigations (either groove or intercalation) were performed using various spectroscopic techniques such as UV-Visible, Fluorescence, and Circular dichroism. The absorption spectra showed a hyperchromic shift in the absorption maxima of ctDNA with successive addition of thiazole derivatives, implying groove binding mode of interactions, further supported by displacement assay and circular dichroism analysis. Furthermore, steady-state fluorescence analysis revealed the static mode of quenching and moderate bindings between the ligand and DNA biomolecule. The competitive studies showed that the derivatives having a pyridinyl (heteroaromatic) group in their structure, bind with the nucleic acid of calf-thymus (ctDNA) more effectively in the minor groove region as compared with the aromatic substitutions.

Visible-Light-Prompted Synthesis and Binding Studies of 5,6-Dihydroimidazo[2,1-b]thiazoles with BSA and DNA Using Biophysical and Computational Methods.

Fused heterocyclic systems containing a bridgehead nitrogen atom have emerged as imperative pharmacophores in the design and development of new drugs. Among these heterocyclic moieties, the imidazothiazole scaffold has long been used in medicinal chemistry for the treatment of various diseases. In this study, we have established a simplistic and environmentally safe regioselective protocol for the synthesis of 5,6-dihydroimidazo[2,1-b]thiazole derivatives from easily available reactants. The reaction proceeds through in situ formation of the α-bromodiketones ensuing trap with imidazolidine-2-thione to provide these versatile bicyclic heterocycles in excellent yields. The synthesized compounds were screened through the molecular docking approach for the most stable complex formation with bovine serum albumin (BSA) and calf thymus deoxyribonucleic acid (ctDNA). The selected compound was further studied using ex vivo binding studies, which revealed moderate interactions with BSA and ctDNA. The binding studies were performed using biophysical approaches including UV-visible spectroscopy, steady-state fluorescence, circular dichroism (CD), and viscosity parameters.

Vision on Synthetic and Medicinal Facets of 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazine Scaffold.

The present review article strives to compile the latest synthetic approaches for the synthesis of triazolothiadiazine and its derivatives, along with their diverse pharmacological activities, viz. anticancer, antimicrobial, analgesic and anti-inflammatory, antioxidant, antiviral, enzyme inhibitors (carbonic anhydrase inhibitors, cholinesterase inhibitors, alkaline phosphatase inhibitors, anti-lipase activity, and aromatase inhibitors) and antitubercular agents. The review focuses particularly on the structure-activity relationship of biologically important 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines, which have profound importance in drug design, discovery and development. In silico pharmacokinetic and molecular modeling studies have also been summarized. It is hoped that this review article will be of help to researchers engaged in the development of new biologically active entities for the rational design and development of new target-oriented 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine-based drugs for the treatment of multifunctional diseases.

Visible-light-mediated regioselective synthesis of novel thiazolo[3,2-b][1,2,4]triazoles: advantageous synthetic application of aqueous conditions.

From a green chemistry perspective, sustainable irradiation as the power source and water as the solvent have certainly grabbed the attention of chemists in recent times because their use helps reduce the hazardous ecological footprints of organic synthesis. In the present work, we have established an efficient, straightforward and green protocol for the regioselective synthesis of novel functionalized thiazolo[3,2-b][1,2,4]triazoles. The visible-light-mediated catalyst-free reaction of diversely substituted α-bromodiketones, generated in situ by the reaction of NBS and 1,3-diketones, with 3-mercapto[1,2,4]triazoles under aqueous conditions afforded thiazolo[3,2-b][1,2,4]triazole derivatives in excellent yields. The structure of the regioisomer has been confirmed explicitly by heteronuclear 2D-NMR [(1H-13C) HMBC, (1H-13C) HMQC] spectroscopic and X-ray crystallographic studies. Radical initiating and trapping experiments supported the free radical mechanism for the cyclization.