Mousa Al-Smadi

Synthesis, Characterization, and Antimicrobial Activity of New 1,2,3-Thiadiazole and 1,2,3-Selenadiazole Derivatives: 1,2,3-Thiadiazole, 1,2,3-selenadiazole, and semicarbazones that are prepared from ketones are promising moieties for lead compound development. New 1,2,3-thiadiazole (2c-4c) and 1,2,3-selenadiazole derivatives (2d4d) were prepared from the corresponding semicarbazones (2b-4b). The semicarbazones (2b-4b) were prepared from the corresponding ketones (2a-4a). Characterization of the synthesized compounds was performed using infrared spectra (IR), proton nuclear magnetic resonance (¹H-NMR) spectra, carbon nuclear magnetic resonance (¹³C-NMR), ultraviolet spectra, mass spectrometry, and elemental analysis. The antimicrobial activity of the prepared compounds was explored in vitro against various pathogenic microbes. All heterocyclic compounds had positive antimicrobial activity, but these activities varied in the extent of antimicrobial coverage. Compounds (2c) and (2d) had positive activity against Staphylococcus aureus and Escherichia coli but without any antipseudomonal activity. Compound (3c) had the most activity against Candida albicans with potential as a novel antifungal agent along with activity against some Gram-positive and Gram-negative bacteria. Compounds (4c) and (4d) exhibited broad-spectrum coverage in which both compounds demonstrated antimicrobial activity against all microorganisms explored. Interestingly, they both had substantial antipseudomonal activity against local resistant Pseudomonas aeruginosa and reference P. aeruginosa (ATCC 27853). This may suggest the potential for compounds (4c) and (4d) as novel broad-spectrum antibacterial agents with promising antipseudomonal activity. In conclusion, new 1,2,3-thiadiazole (2c-4c) and 1,2,3-selenadiazole (2d-4d) derivatives were identified as potential lead compounds for novel antibacterial agents.

New 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives, (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5a), 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5b)), (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6a), and 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6b)), were prepared and screened in vitro for their antimicrobial activity against various pathogenic microbes. In addition, two compounds (5a and 6a) were examined for their in vivo genotoxicity using rats and an 8-hydroxy-2′-deoxyguanosine (8-OHdG) assay. Compounds 5a and 5b were found to be highly active against Gram-positive and Gram-negative bacteria. In addition, a significant inhibition of urinary 8-OHdG level (50.2%) was observed upon treatment of animals with 500 mg/kg body weight (b.w.) of compound 6a (p < 0.0001). However, compound 5a increased urinary 8-OHdG levels. The lethal dose (LD₅₀) values for compounds 5a and 6a were determined by an up-and-down procedure (OECD 425; OECD 1998), which showed that these compounds are safe, since the LD₅₀ was >5000 mg/kg b.w. Thus, the tested compounds might have the potential for use as antibiotics, since they have low genotoxicity and strong antimicrobial activity.

Glyoxalase-I (Glo-I) enzyme was established to be a valid target for anticancer drug design. It performs the essential detoxification step of harmful byproducts, especially methylglyoxal. A robust computer-aided drug design approach was used to design and validate a series of compounds with selenium or sulfur based heterorings. A series of in-house multi-armed 1,2,3-selenadiazole and 1,2,3-thiadiazole benzene derivatives were tested for their Glo-I inhibitory activity. Results showed that these compounds bind Glo-I active sites competitively with strong potential to inhibit this enzyme with IC₅₀ values in micro-molar concentration. Docking poses revealed that these compounds interact with the zinc atom at the bottom of the active site, which plays an essential role in its viability.

The commercially available aromatic polyketones 1a-d were utilized for the synthesis of the multi-arm1,2,3-selenadiazole derivatives 3a-d. The preparation starts with the reaction between compounds 1a-d and p-toluenesulfonyl hydrazide to give the corresponding tosylhydrazones 2a-d. Subsequent reaction with selenium dioxide leads to regiospecific ring closure of the tosylhydrazones to give the target multi-arm 1,2,3-selenadiazole derivatives in high yield. A 1,2,3-selenadiazole derivative 3e containing an epoxide ring was also prepared. The structures of all the synthesized compounds were confirmed on the basis of spectral and analytical data. The compounds were screened in vitro for their antimicrobial activity against various pathogenic bacterial and Candida strains obtained from King Abdullah Hospital in Irbid -Jordan. Compounds 3a, 3c and 3e were found to be highly active against all the selected pathogens. Compound 3e showed an inhibition zone of 13 mm against the highly resistant P. aruginosa.

Magnified image The diketones 2a‐d with different alkyl chain length are used for the synthesis of di‐1,2,3‐thia or selenadiazole derivatives 4a‐d and 5a‐d. The diketones 2a‐d where prepared by a unique method through the reaction between the corresponding dibromoalkanes 1a‐d and ethyl acetoacetate, which are transformed into the corresponding semicarbazone derivatives 3a‐d. The di‐1,2,3‐thia or selenadiazole derivatives 4a‐d and 5a‐d were prepared from the semicarbazones derivatives 3a‐d on oxidative cyclization with thionyl chloride and selenium dioxide respectively in high yield.

The aromatic polyketones 3a-d are versatile compounds for the synthesis of the multi-1,2,3-selenadiazole aromatic derivatives 1a-d. The preparation starts with the reaction between the multi-bromomethylene benzene derivatives 2a-d and 4-hydroxy- acetophenone to give compounds 3a-d which are transformed through the reaction with semicarbazide hydrochloride or ethyl hydrazine carboxylate into the corresponding semicarbazones derivatives 4a-d or hydrazones 5a-d. The reaction with selenium dioxide leads to regiospecific ring closure of semicarbazones or hydrazones to give the multi- 1,2,3-selenadiazole aromatic derivatives in high yield.

New 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives, 14-23, were prepared from the ketones 1-5 via the corresponding semicarbazones or hydrazones 6-12. The Hurd-Mori and Lalezari methods were used, respectively, for the preparation of these 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives. The intermediate 13 was also trapped, separated and fully characterized. These derivatives are important for photocrosslinking processes and due to their potential biological activity.