A facile synthesis and evaluation of new biomolecule-based coumarin–thiazoline hybrids as potent anti-tubercular agents with cytotoxicity, DNA cleavage and X-ray studies

Abstract

An efficient and rapid synthesis of coumarin-thiazoline hybrids (1a-1j) under microwave irradiation has been described in high yields. The synthesized compounds (1a-1l) were characterized by elemental and spectroscopic analysis; in addition, the structures of compound (1a), (1b), (1e) and (1h) have been elucidated by single crystal X-ray diffraction technique. All the newly synthesized compounds were screened for their in-vitro anti-tubercular activity and DNA cleavage study, while the most active compounds were subjected for their cytotoxic assay on Vero cell lines. Among the tested, compound (1b) exhibited excellent anti-tubercular activity MIC 0.09 µg/mL with low level of cytotoxicity, suggesting that compound (1b) is a promising lead for subsequent investigation in search of new anti-tubercular agents. Further, DNA cleavage study by agarose gel electrophoresis method revealed that compounds (1b), (1d), (1f) and (1i) cleaved DNA more efficiently and thereby exhibits nuclease activity.This research paper is dedicated to my beloved Prof. M. V. Kulkarni on his 60 th birthday.From the results, it's clear that none of the compounds violate the rule and they fall well in the range as stated by RO5 to qualify as a drug candidate.Coumarins are an elite class of oxygen-containing fused heterocycles, which are widely distributed in nature, especially in plants. They form a large class of important lactones with a fused structure of benzene and α-pyrone ring, and virtually contain π -π conjugated system with rich electron and good charge transport properties. Moreover, the unique structure of coumarin has a special ability which allows its derivatives readily interact with a diversity of enzymes and receptors in organisms through weak bond interactions and thereby exhibit wide potentiality as medicinal drugs. Hence, coumarin based compounds have attracted special interest in the area of medicinal chemistry and their outstanding contributions in the prevention and treatment of numerous diseases have become an extremely attractive highlight. 4 Recently many coumarin scaffolds have been investigated as potential candidates for the treatment of tuberculosis for e.g., Diaryl coumarin (1), 4 aryl/alkyl sulfonyl methyl coumarin (2), Iodinated-4-aryloxymethylcoumarin (3) and Chalconated coumarin (4) have been reported, to exhibit potent anti-tubercular activity with MICs of 0.24, 0.78, 1.56 and 3.5µg/ml respectively, 5 whereas naturally occurring coumarins such as Ferulenol (5), Suberosin (6), Osthol (7), Scopoletin (8) and Umbelliferone (9) exhibited MICs of 2, 16, 32, 42 and 58.3 µg/ml respectively. 6 Reports have also suggested that coumarin class compounds targets the fatty acyl-ACP synthetase activity of the FadD32 enzyme 5a,6a which is essential for Mtb survival as it plays a critical role in the biosynthesis of the unique branched fatty acids (mycolic acids) that make up the Mtb cell wall. Hence looking into the biological significance of coumarin, particularly in the field of tuberculosis, we anticipate that coumarin cou...

Efficient Synthesis of 2,4,5‐Substituted Thiazoles via Intramolecular Knoevenagel Condensation–Cyclization Reaction Using TEA under Microwave Irradiation Conditions

“…Novel 2,4,5‐substituted thiazole‐coumarins ( 1 a‐1 o ) were synthesized and isolated, by reaction of substituted 4‐bromomethyl coumarins ( a–e ) and benzoyl thioureas (1‐3) (Scheme ‐ 1). Priory the substituted 4‐bromomethyl coumarins ( a–e ) synthesized by the Pechman cyclization of substituted phenols and ethyl 4‐bromoacetoacetate and benzoyl thioureas were prepared from earlier reports as follow; Benzoyl chloride (5 mmol) was taken in acetone and added slowly to of KSCN (5 mmol) in acetone solution, refluxed for half an hr and cool the reaction mass on ice bath. Then secondary amine (5 mmol) in acetone was added slowly with constant stirring and further stirred for 2 h. The solution mass was quenched onto ice; precipitated product is filtered and recrystallized to get pure products.…”

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis

“… 22 When Doxorubicin is conjugated with the BR96-monoclonal antibody via the thioether linkage, its anticancer activity increases. 23 Although the thioether linkage is thought to increase drug likeness by improving pharmacokinetic features, thioetherification (C–S bond formation) has received less attention and resources than C–C, C–N, and C–O bond formation. 24 , 25 …”

Microwave assisted synthesis of coumarin-purine derivatives: An approach to in vitro anti-oxidant, DNA cleavage, crystal structure, DFT studies and Hirshfeld surface analysis

“…Similarly, compounds 3a (C6-CH 3 ) and 3j (C6- tert butyl ) substitutions in the coumarin ring have shown excellent anti-TB activity. Recently, our group designed and synthesized several coumarin derivatives with DNA cleavage studies [29, 30], such as coumarin-thiazoline and coumarin-maltol. These research works motivated us to conduct further investigation of coumarin-purine derivatives such as, microwave synthesis, in vitro anti-oxidant, DNA cleavage, Crystal structure, DFT studies and Hirshfeld surface analysis.…”