Biological Activity Tuning Of Antibacterial Urotropine Via Co-Crystallization: Synthesis, Biological Activity Evaluation And Computational Insight

Urotropine (1) is a synthetic heterocyclic antibacterial agent. We have synthesized co-crystals of urotropine (1) with syringic acid, 4-14-(trifluoromethyl)phenoxylphenol, and trans-cinnamic acid in a 1:1 stoichiometric ratio by using the neat grinding method. The structures of synthesized co-crystals 2-4 were studied via FT-IR spectroscopy, thermal analysis, density functional theory calculations and single crystal X-ray diffraction techniques. In vitro biological activity evaluation indicated that co-crystals 2-4 are potential urease inhibitors and anti-leishmanial agents. Co-crystals 2 (IC50 = 6.5 +/- 0.31 mu M) and 3 (IC50 = 19.9 +/- 0.75 mu M) appeared as potent urease inhibitors, whereas co-crystal 4 (IC50 = 34.0 +/- 2.13 mu M) showed a significant urease inhibition activity against the tested standard acetohydroxamic acid (IC50 = 20.3 +/- 0.43 mu M). Furthermore, co-crystal 2 (IC50 = 34.27 +/- 1.2 mu g mL(-1)), co-crystal 3 (IC50 = 22.78 +/- 2.8 mu g mL(-1)), and cocrystal 4 (IC50 = 24.82 +/- 1.4 mg mL(-1)) exhibited significant anti-leishmanial activity in comparison to standard drugs, amphotericin B (IC50 = 0.39 +/- 10.05 mu g mL(-1)) and pentamidine (IC50 = 3.15 +/- 0.005 mu g mL(-)(1)). All synthesized co-crystals 2-4 were found to be non-cytotoxic against the 3T3 normal fibroblast cell line. To the best of our knowledge, the synthesis of co-crystals 2 and 3, and the biological activities of all the synthesized co-crystals 2-4 are reported here for the first time.