Streptomycin hydrazone derivatives: synthesis and molecular recognition in aqueous solution

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Biophysical Chemistry

Background:

• Streptomycin, a vital antibiotic, has derivatives that may possess unique binding and therapeutic properties.
• Understanding molecular interactions is crucial for developing novel therapeutic agents.
• Nucleotide binding mechanisms often involve complex interplay of forces beyond simple electrostatics.

Purpose of the Study:

• To synthesize and characterize novel hydrazone derivatives of streptomycin.
• To investigate the binding affinities of these derivatives with dicarboxylates and adenine nucleotides.
• To explore the antibiotic activity of the synthesized derivatives compared to native streptomycin.

Main Methods:

• Synthesis and characterization of five streptomycin hydrazone derivatives using IR, NMR, mass spectrometry, and elemental analysis.
• Potentiometric and 1H NMR titrations to determine protonation constants and binding affinities.
• Density Functional Theory (DFT) calculations to analyze complex structures and interactions.

Main Results:

• Five streptomycin hydrazone derivatives (D0h, D1ph, D2bt, D3dctf, D4ag) were successfully synthesized and characterized.
• D1ph and D2bt derivatives exhibited high affinity for AMP and ATP, respectively, highlighting the importance of conformational fit over electrostatic forces.
• DFT analysis revealed that multiple interactions stabilize the complexes between D1ph derivatives and nucleotides (AMP, ADP).

Conclusions:

• Streptomycin derivatives can be designed to selectively bind nucleotides, with conformational complementarity playing a key role.
• The synthesized derivatives show potential for further investigation as therapeutic agents, possibly with modified antibiotic profiles.
• This study provides insights into the molecular basis of streptomycin derivative-nucleotide interactions, informing future drug design.