Design, synthesis, ADME prediction and pharmacological evaluation of novel benzimidazole-1,2,3-triazole-sulfonamide hybrids as antimicrobial and antiproliferative agents
Autor: | Sanaa K. Bardaweel, El Sayed H. El Ashry, Pramod K. Sahu, Meshal A. Almehmadi, Nadjet Rezki, Fawzia F. Al-blewi, Mouslim Messali, Mohamed Reda Aouad |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
Benzimidazole
1 2 3-Triazole Antiproliferative activity Antimicrobial activity 01 natural sciences chemistry.chemical_compound 1 2 3-Triazoles QD1-999 ADME chemistry.chemical_classification Sulfonamides 010405 organic chemistry General Chemistry Click synthesis Antimicrobial Combinatorial chemistry 0104 chemical sciences Sulfonamide 010404 medicinal & biomolecular chemistry Chemistry ADMET chemistry Lipinski's rule of five Benzimidazoles Azide Pharmacophore Research Article |
Zdroj: | Chemistry Central Journal, Vol 12, Iss 1, Pp 1-14 (2018) Chemistry Central Journal |
Popis: | Background Nitrogen heterocyclic rings and sulfonamides have attracted attention of several researchers. Results A series of regioselective imidazole-based mono- and bis-1,4-disubstituted-1,2,3-triazole-sulfonamide conjugates 4a–f and 6a–f were designed and synthesized. The first step in the synthesis was a regioselective propargylation in the presence of the appropriate basic catalyst (Et3N and/or K2CO3) to afford the corresponding mono-2 and bis-propargylated imidazoles 5. Second, the ligation of the terminal C≡C bond of mono-2 and/or bis alkynes 5 to the azide building blocks of sulfa drugs 3a–f using optimized conditions for a Huisgen copper (I)-catalysed 1,3-dipolar cycloaddition reaction yielded targeted 1,2,3-triazole hybrids 4a–f and 6a–f. The newly synthesized compounds were screened for their in vitro antimicrobial and antiproliferative activities. Among the synthesized compounds, compound 6a emerged as the most potent antimicrobial agent with MIC values ranging between 32 and 64 µg/mL. All synthesized molecules were evaluated against three aggressive human cancer cell lines, PC-3, HepG2, and HEK293, and revealed sufficient antiproliferative activities with IC50 values in the micromolar range (55–106 μM). Furthermore, we conducted a receptor-based electrostatic analysis of their electronic, steric and hydrophobic properties, and the results were in good agreement with the experimental results. In silico ADMET prediction studies also supported the experimental biological results and indicated that all compounds are nonmutagenic and noncarcinogenic. Conclusion In summary, we have successfully synthesized novel targeted benzimidazole-1,2,3-triazole-sulfonamide hybrids through 1,3-dipolar cycloaddition reactions between the mono- or bis-alkynes based on imidazole and the appropriate sulfonamide azide under the optimized Cu(I) click conditions. The structures of newly synthesized sulfonamide hybrids were confirmed by means of spectroscopic analysis. All newly synthesized compounds were evaluated for their antimicrobial and antiproliferative activities. Our results showed that the benzimidazole-1,2,3-triazole-sulfonamide hybrids inhibited microbial and fungal strains within MIC values from 32 to 64 μg/mL. The antiproliferative evaluation of the synthesized compounds showed sufficient antiproliferative activities with IC50 values in the micromolar range (55–106 μM). In conclusion, compound 6a has remarkable antimicrobial activity. Pharmacophore elucidation of the compounds was performed based on in silico ADMET evaluation of the tested compounds. Screening results of drug-likeness rules showed that all compounds follow the accepted rules, meet the criteria of drug-likeness and follow Lipinski’s rule of five. In addition, the toxicity results showed that all compounds are nonmutagenic and noncarcinogenic. |
Databáze: | OpenAIRE |
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