Molecular design and QSAR study of low acute toxicity biocides with 4,4′-dimorpholyl-methane core obtained by microwave-assisted synthesis

The solventless microwave-assisted synthesis of aldehydes (1a, 2b–h) and morpholine (3) in 1: 2 (aldehyde: morpholine) ratio yielded eight 4,4′-dimorpholyl-methanes (4a–4h), which were thoroughly characterized through FT-IR,¹H,¹³C and 2D NMR, confirming structures of type 4. The described compounds are dimorpholino-methane (4a), 2-(dimorpholinomethyl)-phenol (4b), 4-bromo-2-(dimorpholinomethyl)-phenol (4c), 2,4-di-tert-butyl-6-(dimorpholinomethyl)-phenol (4d), 4,4′-(pyridin-2-ylmethylene)-dimorpholine (4e), 4,4′-((4-iso-propylphenyl)methylene)-dimorpholine (4f), 4,4′-(naphthalen-1-ylmethylene)-dimorpholine (4g) and 4,4′-(pyren-1-ylmethylene)-dimorpholine (4h). Additionally, single crystal X-ray diffraction analysis for 4b, 4c, 4d and 4e derivatives was accomplished showing interesting geometrical features. The obtained 4,4′-dimorpholyl-methanes were subjected for two biological tests, (i) acute toxicity, related to Photobacterium phosphoreum (Vibrio fischeri), and (ii) biocidal activities, determined for B. subtilis, E. coli and Ps. fluorescence strains. The results show that 4a–h compounds have varying degrees of toxicity, classified as 4a, 4b, 4c, 4e and 4f as slightly to moderately toxic agents, 4g and 4h as highly toxic chemicals, and 4d as an extremely toxic compound. Besides, the biocidal activities, which is controlled mainly by the substituent directly bonded to the methinic bridge (named C5, which originally is the carbon atom of the aldehyde functionality), have shown varying degrees of inhibitory effects on the growth of selected strains, depending on the chemical structure of 4a–h. A QSAR study was developed, and quantum-chemical parameters of 4a–h were obtained with the DFT approach at the B3LYP/6-311G(d) level of theory in the gas phase. Hence ten molecular descriptors were determined, being E_HOMO, E_LUMO, GAP, C5 Mulliken atomic charge (AC_Mulliken), C5 atomic charge of NBO (AC_NBO), dipolar moment (μ), molecular hydrophobicity as log P, molecular volume (Vol), electrostatic potential (ESP) and δ¹³C(C5), all of them being typical determinants of biological activities in other, different or related, molecular systems. A linear combination from three to six molecular descriptors was chosen as a multivariate model to achieve correlations in order to relate them to their acute toxicity and understand the obtained trend. Three sets of descriptors accomplished the statistical goal, and through an identity analysis the conserved descriptors in these three series are log P, the ESP and the δ¹³C(C5), which seemed to be the tracking variables in the system. To a lesser extent, the frontier orbitals and their relations (HOMO, LUMO and GAP) are also present within the correlations. The phenol-bearing structures (4b, 4c and 4d, derived from salicylidenes) are best tuned within these variables since the substitution in the phenol fragment both governs the toxicity and the biocidal potency. Finally, we can guarantee that the best candidates in this series are 4a, 4b and 4c, because diminished toxicity and preserved biocidal potency were obtained at the same time. A more hydrophobic substitution (4d) extremely increases the Vibrio fischeri toxicity, ruling out its application. Through the full analysis presented in this piece of work it can be stated that selected prototypes could be used in industrial facilities, particularly in the petroleum industry, as a new generation of ecological chemical products.