Abstract
In continuation of our endeavor towards the development of potent and effective antimicrobial agents, three series of halophenyl bis-hydrazones (14a–n, 16a–d, 17a and 17b) were synthesized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the identification of five molecules 14c, 14g, 16b, 17a and 17b (MIC range from 0.12 to 7.81 μg/mL) with broad antimicrobial activity against Mycobacterium tuberculosis; Aspergillus fumigates; Gram positive bacteria, Staphylococcus aureus, Streptococcus pneumonia, and Bacillis subtilis; and Gram negative bacteria, Salmonella typhimurium, Klebsiella pneumonia, and Escherichia coli. Three of the most active compounds, 16b, 17a and 17b, were also devoid of apparent cytotoxicity to lung cancer cell line A549. Amphotericin B and ciprofloxacin were used as references for antifungal and antibacterial screening, while isoniazid and pyrazinamide were used as references for antimycobacterial activity. Furthermore, three Quantitative Structure Activity Relationship (QSAR) models were built to explore the structural requirements controlling the different activities of the prepared bis-hydrazones.
Highlights
Despite the harmful impact of microbial threats to public health, large pharmaceutical companies have left the area of antimicrobial discovery and the number of scientists involved in the search for novel broad antimicrobial leads was reduced dramatically [1]
22.9 ± 0.58 nt NA: No Activity; The screening organisms, Mould: Aspergillus fumigatus (RCMB 02568, Af); Gram positive bacteria: Staphylococcus aureus (RCMB 010028, Sa), Streptococus pneumoniae (RCMB 010010, Sp), and Bacillus subtilis (RCMB 010069, Bs); Gram negative bacteria: Pseudomonas aeruginosa (RCMB 010043, Pa), Salmonella typhimurium (RCMB 010315, St), Klebsiella penumoniae (RCMB 0010093, Kp) and Escherichia coli (RCMB 010052, Ec); AB: Amphotericin B; CF: Ciprofloxacin; Comp.: Compound; nt: not tested; Results shown in bold letters indicate more antituberculosis activity of compounds compared to others
The results evidenced that compounds 14c, 14g, 16b, 17a and 17b can be considered as broad spectrum antimicrobials against aspergillosis, Gram positive bacteria and Gram negative bacteria
Summary
Despite the harmful impact of microbial threats to public health, large pharmaceutical companies have left the area of antimicrobial discovery and the number of scientists involved in the search for novel broad antimicrobial leads was reduced dramatically [1]. The longer duration of TB therapy and the increasing incidences of tuberculosis in immunocompromised patients emphasize the urgent need for discovery of new lead compounds to extend the range of effective TB treatment options [11,12,13]. Owing to their significant biological and pharmacological profiles, hydrazides and hydrazones have stood out as a prime scaffold for the discovery of innovative therapies. We described three valid 2D-QSAR models in order to explore the structural requirements controlling these observed antibacterial and antitubercular activities
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