Design, synthesis, biological screening and molecular docking studies of novel multifunctional 1,4-di (aryl/heteroaryl) substituted piperazine derivatives as potential antitubercular and antimicrobial agents

[Display omitted] •A series of novel multifunctional 1, 4-di (aryl/heteroaryl) substituted piperazine derivatives were synthesized.•Novel piperazine derivatives were screened for antitubercular, antimicrobial and cytotoxic properties.•7a exhibited very good activity (MIC = 0.65 µg/mL) against Mtb H3...

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Bibliographic Details
Published in:	Bioorganic chemistry Vol. 119; p. 105568
Main Authors:	Mekonnen Sanka, Bruktawit, Mamo Tadesse, Dereje, Teju Bedada, Endale, Mengesha, Ephriem T., Babu G., Neelaiah
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-02-2022
Subjects:	Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antifungal Agents - chemical synthesis Antifungal Agents - chemistry Antifungal Agents - pharmacology Antimicrobial activity Antitubercular activity Aspergillus niger - drug effects Cytotoxicity Dose-Response Relationship, Drug Drug Design Drug Evaluation, Preclinical Escherichia coli - drug effects Fusarium - drug effects Microbial Sensitivity Tests Molecular docking Molecular Docking Simulation Molecular Structure Mycobacterium tuberculosis - drug effects Piperazine derivatives Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Staphylococcus aureus - drug effects Structure-Activity Relationship Synthesis Cytotoxicity Antimicrobial activity Synthesis Piperazine derivatives Antitubercular activity Molecular docking
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Summary:	[Display omitted] •A series of novel multifunctional 1, 4-di (aryl/heteroaryl) substituted piperazine derivatives were synthesized.•Novel piperazine derivatives were screened for antitubercular, antimicrobial and cytotoxic properties.•7a exhibited very good activity (MIC = 0.65 µg/mL) against Mtb H37Rv among the tested novel compounds.•The antitubercular activity results were supported by the molecular docking studies.•Docking studies revealed that high binding affinity toward bacterial DNA dependent RNA polymerase (Mtb RNAP). In this paper, two series of novel multifunctional 1, 4-di (aryl/heteroaryl) substituted piperazine derivatives (6a-d &7a-d) were synthesized, characterized, and evaluated for their antitubercular, antibacterial, and antifungal activities. A step-wise reduction, bromination and substitution reactions on various aldehydes resulted in alcohols (2a–d), bromides (3a–d), and titled novel compounds (6a–d &7a–d) in moderate to good yields (48–85%). The novel compounds were evaluated for their antitubercular and antimicrobial activities. Compound 7a exhibited promising antitubercular activity (MIC: 0.65 µg/mL) almost equal to the Rifampicin, while the rest of the compounds were moderately active against MTB H37Rv except 6b. Compounds 7a and 6b showed good activity against tested fungal pathogens. Compounds 7a and 7b were proven as the best bacterial agents. Molecular docking studies were in agreement with the in-vitro results. Docking analyses show that all the synthesized molecules bind to the target protein Mtb RNAP (PDB ID: 5UHC) fairly strongly. All the compounds were evaluated for their in vitro cytotoxicity effect using the MTT assay method against human cancer cell line MCF-7. The compounds demonstrated growth inhibitory effect on the cell line with significant IC50 values ranging between 8.20 and 34.45 µM. Most importantly, compound 7a displayed good binding affinity towards the tested protein with binding energy −7.30 kcal/mol and a stronger hydrogen bond distance of 2.2 Å with ASN-493 residue. Thus, the present research highlighted the potential role of novel piperazine derivatives as potential antitubercular, and antimicrobial candidates and further good research into optimization might result in the development of new antitubercular drug candidates.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0045-2068 1090-2120
DOI:	10.1016/j.bioorg.2021.105568