Design, synthesis and antibacterial activity of minor groove binders: The role of non-cationic tail groups

Abstract

The design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups.

Synthesis and structure–activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents

“…The results of antibacterial screening revealed that, in general, the bis-phenyl derivatives (21)(22)(23)(24)(25)(26)(27) Replacement of one amidino-benzimidazole group in symmetrical compounds 18-20…”

“…These antibacterial activity. MICs against sensitive S. aureus are ≤ 0.5 µg/mL for compounds I and II and 6.25 and 50 µg/mL for compound III and distamycin, respectively [12,21,23,25].…”

“…Synthesized compounds are divided in eight structural groups: i) bis-phenyl-(21)(22)(23)(24)(25)(26), ii) bis-benzimidazole-(18)(19)(20), iii) bis-carboxamidophenyl-(para 27-31), iv) biscarboxamidophenyl-(meta 32,33), v) cyano-amidine (9-11), vi) nitro-amidine(12)(13)(14), vii) amino-amidine(15)(16)(17) and viii) miscellaneous derivatives(34 and 35). Compound 34 is derivative of compound 31 with Ar 2 and R 2 replaced by ethyl ester, while compound 35 is a derivative of compound 21 with the end groups and aromates inversely arranged.…”

Structural insights on the molecular recognition patterns between N6-substituted adenines and N-(aryl-methyl)iminodiacetate copper(II) chelates

“…Indeed, the minor groove is a relevant hydrogen acceptor group that could interact with enzymes, proteins or other active molecules and/or metal complexes. Thus, several promising minor groove binders have showed different biological activities such as antitumoral, antiprotozoal or antibacterial properties [44][45][46][47] and even other approaches regarding gene expression [48]. Therefore the interaction between different organic compounds and/or metal complexes with the N3(purine-like) donor is a topic of increasing interest and encourage further researches regarding the rational design of new biomimetic systems with biological and/or pharmaceutical applications.…”

Systematic synthetic and biophysical development of mixed sequence DNA binding agents

“…This is in spite of significant efforts in chemical biology for over a decade to find methods to systematically modulate cellular transcription factor activity. Complementing the successful polyamides with compounds that have different recognition modules with enhanced cellular uptake and improved solution properties would be an important major advance in the effort to target specific protein binding to nuclear DNA (1, 7, 21–24). …”