The applications of thioureas in crystal engineering have increased dramatically over the past few years. However, their analogs namely N-imino thioureas/thiosemicarbazones are largely ignored, despite the fact that these can be more interesting with respect to crystal engineering applications due to the presence of an additional N-imino moiety. Aiming to highlight their importance in crystal engineering/ supramolecular chemistry, three structurally related coumarin-thiosemicarbazone hybrids (3a-3c) have been designed, synthesized and crystallographically characterized. All of the compounds showed a general preference for the adoption of the cis, trans conformation around the central thiourea moiety; a conformation which is ideal for the formation of a dimeric hydrogen-bonded R 2 2 (8){Á Á ÁH-N-CQS} 2 synthon as the building block. Therefore, this dimeric synthon is observed in all of the compounds, regardless of the formation of layered to cage-like three dimensional supramolecular networks depending on different substituents. The prevalence of the cis, trans conformation and the robustness of the thioamide dimer synthon in thiosemicarbazones indicate its potential use as a design element in crystal engineering.

A series of coumarin-based thiosemicarbazones and their metal complexes have been synthesized and their in vitro potency against urease was evaluated. Single crystal X-ray crystallographic studies were made for compound 14 to investigate the solid state self-assembly which exposed preference of S-conformation owing to intramolecular hydrogen bonding. In vitro urease inhibition assay revealed coumarin-thiosemicarbazone 12 as the most potent inhibitor (IC 50 value of 2.23 ± 0.14 µM) compared to thiourea, used as standard (IC 50 value of 21.25 ± 0.15 µM). Similarly, compounds 4, 6, 7, 9, 15 & 16 showed excellent urease inhibition activity with IC 50 values ranging from 4.15 ± 0.17 to 16.95 ± 0.12 µM. Furthermore, the compounds 3, 8, 11 & 13 also showed good activities (IC 50 values ranging from 33.86 ± 0.12 to 43.12 ± 0.19 µM)against this enzyme. However, the metal complexes of these compounds attributed low activity against urease. Molecular docking with the most cogent ligand against urease was also performed to assess the putative binding mode of the synthesized compounds. Potent compound 12 can serve as potential lead for further chemical tuning towards drug candidate development.In summary, a series of coumarin-based thiosemicarbazone ligands 3-18 and their metal complexes 19-52 have been synthesized and evaluated for urease inhibition. The synthesized compounds were characterized through spectroscopic analysis and X-ray diffraction technique was used to determine the solid state self-assembly of compound 14. In urease inhibition assay, coumarin-based thiosemicarbazone 12 with IC 50 value of 2.23 ± 0.14 µM was found to be the most active compound in the series. Compounds 6 and 15 were also found to be highly potent antiurease molecules with IC 50 values of 4.93 ± 0.11 and 4.15 ± 0.17 µM, respectively. The other compounds of the series showed good to moderate antiurease potential. However, most of the metal complexes were found inactive in this assay. The molecular docking study of compound 12 explored the putative binding modes of these compounds in the enzyme pocket. The highly active compounds i.e. 6, 12 and 15 against urease could be further modified to serve as potential lead candidates. Experimental General InformationMelting points were taken on a Fisher-Johns melting point apparatus and are uncorrected.Elemental analyses were performed on a Leco CHNS-9320 (USA) elemental analyzer. Infrared spectra (KBr discs) were run on Shimadzu Prestige-21 FT-IR spectrometer. The 1 H-NMR spectra were recorded in CDCl 3 or DMSO-d 6 on Bruker-500MHz spectrometer, operating at 500 MHz and at 125 MHz for 13 C-NMR using TMS as an internal standard. 1 H chemical shifts are reported in δ/ppm and coupling constants in Hz. The electron impact mass spectra (EIMS) were determined with JEOL MS Route mass spectrometer. The progress of the reaction and purity of the products were checked on TLC plates coated with Merck silica gel 60 GF254, and the spots

Thiosemicarbazones (5a–5j) have been synthesized from 2,3,4,4a-tetrahydroxanthen-1-one, obtained in high yield through Me3N-promoted domino Baylis–Hillman/oxa-Michael reaction. Their solid-state self-assembly and antimicrobial properties are studied.

The title compound (III) is synthesized in high yield by Me3N‐promoted domino Baylis—Hillman/oxa‐Michael reaction sequence and smoothly converted into xanthene‐based thiosemicarbazones (V).