Synthesis, Structural Properties and Biological Activities of Novel Hydrazones of 2-, 3-, 4-Iodobenzoic Acid

Abstract

Nowadays, searching for novel antimicrobial agents is crucial due to the increasing number of resistant bacterial strains. Moreover, cancer therapy is a major challenge for modern medicine. Currently used cytostatics have a large number of side effects and insufficient therapeutic effects. Due to the above-mentioned facts, we undertook research to synthesize novel compounds from the acylhydrazone group aimed at obtaining potential antimicrobial and anticancer agents. As a starting material, we employed hydrazides of 2-, 3- or 4-iodobenzoic acid, which gave three series of acylhydrazones in the condensation reaction with various aldehydes. The chemical structure of all obtained compounds was confirmed by IR, ¹H NMR, and ¹³C NMR. The structure of selected compounds was determined by single-crystal X-ray diffraction analysis. Additionally, all samples were characterized using powder X-ray diffraction. The other issue in this research was to examine the possibility of the solvent-free synthesis of compounds using mechanochemical methods. The biological screening results revealed that some of the newly synthesized compounds indicated a beneficial antimicrobial effect even against MRSA-the methicillin-resistant Staphylococcus aureus ATCC 43300 strain. In many cases, the antibacterial activity of synthesized acylhydrazones was equal to or better than that of commercially available antibacterial agents that were used as reference substances in this research. Significantly, the tested compounds do not show toxicity to normal cell lines either.

Keywords: acylhydrazones; antimicrobial activity; bioactivity; crystal structure; cytotoxicity; iodobenzoic acid derivatives.

Scheme 1

Synthesis of the hydrazides of 2-, 3- or 4-iodobenzoic acid.

Scheme 2

Synthesis of the acylhydrazones of 2-, 3- or 4-iodobenzoic acid.

Figure 1

PXRD patterns of compound 13: (a) simulated from the SCXRD data; (b) experimental after synthesis from solution; (c–e) experimental after liquid-assisted grinding (LAG) for 30, 60 and 90 min, respectively, using ethanol as a solvent; (f) experimental after LAG for 90 min using acetonitrile.

Figure 2

Perspective view of the molecules constituting the asymmetric part in crystals 13, 13∙ACN, 20 and 26a with the atom-numbering scheme. Thermal ellipsoids are drawn at the 50% probability level. Dashed lines indicate the hydrogen bonds.

Figure 3

Molecular overlay of the conformers found in: (a) polymorphic modifications 26a (red line), 26b (green line) and 26c (dark blue line); (b) unsolvated crystal 13 (molecule 13A—blue line, molecule 13B—green line) and its solvate 13∙ACN (pink line).

Figure 4

Part of the crystal structure of 13·ACN in view along the a axis, showing the formation of channels filled in by the solvent molecules.

Figure 5

Part of the crystal structure of 9 showing (a) supramolecular chains stabilized via strong N1–H1n∙∙∙O1A/N1A–H1nA∙∙∙O1 (x, y + 1, z) hydrogen bonds and weak C–H∙∙∙O/π interactions; (b) crystal packing viewed along the b axis with marked 2D layer parallel to the (−102) crystallographic plane. Molecules 9-A and 9-B are marked in green and blue, respectively. Dashed lines indicate hydrogen bonds.

Figure 6

(a) Part of the crystal structure of 26a showing hydrogen-bonding motifs; (b) crystal packing in 26a viewed along the b axis; (c) crystal packing in 26b viewed down the a axis; (d) hydrogen-bonding patterns in crystal 26c, (e) part of the crystal structure of 26c in view along the a axis. Dashed lines indicate inter- and intramolecular interactions.