Synthesis, anti-mycobacterial activity and DNA sequence-selectivity of a library of biaryl-motifs containing polyamides.
The alarming rise of extensively drug-resistant tuberculosis (XDR-TB) strains, compel the development of new molecules with novel modes of action to control this world health emergency. Distamycin analogues containing N-terminal biaryl-motifs 2(1-5)(1-7) were synthesised using a solution-phase approach and evaluated for their anti-mycobacterial activity and DNA-sequence selectivity. Thiophene dimer motif-containing polyamide 2(2,6) exhibited 10-fold higher inhibitory activity against Mycobacterium tuberculosis compared to distamycin and library member 2(5,7) showed high binding affinity for the 5'-ACATAT-3' sequence.
School of Science and Sport, Institute of Biomedical and Environmental Health Research (IBEHR), University of the West of Scotland, Paisley PA1 2BE, UK. Electronic address: federico.brucoli@uws.ac.uk.
Federico
F
Brucoli
Mycobacteria Research Laboratory, Department of Biological Sciences, The Institute of Structural and Molecular Biology, Birkbeck, University of London, London WC1E 7HX, UK.
Juan D
JD
Guzman
Mycobacteria Research Laboratory, Department of Biological Sciences, The Institute of Structural and Molecular Biology, Birkbeck, University of London, London WC1E 7HX, UK.
Arundhati
A
Maitra
UCL School of Pharmacy, London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Colin H
CH
James
Centre for Biological Sciences, Life Sciences Building 85, University of Southampton, Southampton SO17 1BJ, UK.
Keith R
KR
Fox
Mycobacteria Research Laboratory, Department of Biological Sciences, The Institute of Structural and Molecular Biology, Birkbeck, University of London, London WC1E 7HX, UK.
Sanjib
S
Bhakta
D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018983:DNA Footprinting; D004269:DNA, Bacterial / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004214:Distamycins / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development; D009757:Nylons / Q000138:chemical synthesis* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry
D000995:Antitubercular Agents; D004269:DNA, Bacterial; D004214:Distamycins; D008024:Ligands; D009757:Nylons; D054852:Small Molecule Libraries; D013876:Thiophenes
Anti-tubercular agents; Antibiotic resistance; Combinatorial chemistry; DNA-minor groove ligands; Distamycin; Whole cell phenotypic evaluation