Lavanya Gopala

Design, synthesis and antimicrobial evaluation of novel benzimidazole-incorporated sulfonamide analogues

A novel series of benzimidazole-incorporated sulfonamide analogues were designed and synthesized with an effort to overcome the increasing antibiotic resistance. Compound 5c gave potent activities against Gram-positive bacteria and fungi, and 2,4-dichlorobenzyl derivative 5g showed good activities against Gram-negative bacteria. Both of these two active molecules 5c and 5g could effectively intercalate into calf thymus DNA to form compound-DNA complex respectively, which might block DNA replication to exert their powerful antimicrobial activity. Molecular docking experiments suggested that compounds 5c and 5g could insert into base-pairs of DNA hexamer duplex by the formation of hydrogen bonds with guanine of DNA. The transportation behavior of these highly active compounds by human serum albumin (HSA) demonstrated that the electrostatic interactions played major roles in the strong association of active compounds with HSA, and which was also confirmed by the full geometry calculation optimizations.

Novel benzimidazolyl tetrahydroprotoberberines: Design, synthesis, antimicrobial evaluation and multi-targeting exploration

A series of novel benzimidazolyl tetrahydroprotoberberines were conveniently designed and efficiently synthesized from berberine via direct cyclization of tetrahydroprotoberberine aldehyde and o-phenylene diamines under metal-free aerobic oxidation. All the new compounds were characterized by IR, 1H NMR, 13C NMR and HRMS spectra. The antimicrobial evaluation revealed that the 5-fluorobenzimidazolyl derivative 5b was the most active antibacterial and antifungal molecule with broad spectrum in comparison to Berberine, Chloromycin, Norfloxacin and Fluconazole. It triggered almost no resistance development against MRSA even after 15 passages. Further studies demonstrated that compound 5b could not only effectively interact with Topo IA by hydrogen bonds, but also intercalate into calf thymus DNA and cleave pBR322 DNA, which might be responsible for its powerful bioactivities.

Novel potentially antifungal hybrids of 5-flucytosine and fluconazole: Design, synthesis and bioactive evaluation

A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by 1H NMR, 13C NMR, IR and HRMS spectra. Bioactive assay manifested that some prepared compounds showed moderate to good antifungal activities in comparison with fluconazole and 5-flucytosine. Remarkably, the 3,4-dichlorobenzyl hybrid 7h could inhibit the growth of C. albicans ATCC 90023 and clinical resistant strain C. albicans with MIC values of 0.008 and 0.02 mM, respectively. The active molecule 7h could not only rapidly kill C. albicans but also efficiently permeate membrane of C. albicans. Molecular docking study revealed that compound 7h could interact with the active site of CACYP51 through hydrogen bond. Quantum chemical studies were also performed to explain the high antifungal activity. Further preliminary mechanism research suggested that molecule 7h could intercalate into calf thymus DNA to form a steady supramolecular complex, which might block DNA replication to exert the powerful bioactivities.

Discovery of novel nitroimidazole enols as Pseudomonas aeruginosa DNA cleavage agents

A series of nitroimidazole enols as new bacterial DNA-targeting agents were for the first time designed, synthesized and characterized by NMR, IR and HRMS spectra. The antimicrobial screening revealed that 2-methoxyphenyl nitroimidazole enol 3i possessed stronger anti-P. aeruginosa efficacy (MIC = 0.10 μmol/mL) than reference drugs Norfloxacin and Metronidazole. Time-kill kinetic assay manifested that the active molecule 3i could rapidly kill the tested strains. Molecular docking indicated that the interactions between compound 3i and topoisomerase II were driven by hydrogen bonds. Quantum chemical study was also performed on 3i to understand the structural features essential for activity. Further research found that compound 3i was not able to effectively intercalate into bacterial DNA but could cleave DNA isolated from the standard P. aeruginosa strain, which might block DNA replication to exert the efficient bioactivities, and this active molecule was also able to be stored and carried by human serum albumin via hydrophobic interactions and hydrogen bonds.

Discovery of natural berberine-derived nitroimidazoles as potentially multi-targeting agents against drug-resistant Escherichia coli

A series of natural berberine-derived nitroimidazoles as novel antibacterial agents were designed, synthesized and characterized by nuclear magnetic resonance (NMR), infrared spectra (IR), and high resolution mass spectra (HRMS) spectra. The antimicrobial evaluation showed that some target molecules exhibited moderate to good inhibitory activities against the tested bacteria and fungi including clinical drug-resistant strains isolated from infected patients. Especially, 2-fluorobenzyl derivative 8f not only gave strong activity against drug-resistant E. coli with the minimal inhibitory concentration (MIC) value of 0.003 mM, 33-fold more active than norfloxacin, but also exhibited low toxicity toward RAW 264.7 cells and less propensity to trigger resistance. The aqueous solubility and ClogP values of target compounds were investigated to elucidate the structureactivity relationships. Molecular docking and quantum chemical studies for compound 8f rationally explained its antibacterial effect. The further exploration of antibacterial mechanism revealed that the highly active compound 8f could effectively permeabilize E. coli cell membrane and intercalate into DNA isolated from resistant E. coli to form 8f-DNA complex that might block DNA replication to exert the powerful bioactivities. Compound 8f could also selectively address resistant E. coli from a mixture of various strains.

Novel Naphthalimide Aminothiazoles as Potential Multitargeting Antimicrobial Agents

A series of novel naphthalimide aminothiazoles were developed for the first time and evaluated for their antimicrobial activity. Some prepared compounds possessed good inhibitory activity against the tested bacteria and fungi. Noticeably, the piperazine derivative 4d displayed superior antibacterial activity against MRSA and Escherichia coli with MIC values of 4 and 8 μg/mL, respectively, to reference drugs. The most active compound 4d showed low toxicity against mammalian cells with no obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy and efficient membrane permeability. Preliminarily investigations revealed that compound 4d could not only bind with gyrase-DNA complex through hydrogen bonds but could effectively intercalate into MRSA DNA to form 4d-DNA supramolecular complex, which might be responsible for the powerful bioactivity. Further transportation behavior evaluation indicated that molecule 4d could be effectively stored and carried by human serum albumin, and the hydrophobic interactions and hydrogen bonds played important roles in the binding process.