Molar ratios of therapeutic water-soluble phenothiazine·water-insoluble phospholipid adducts reveal a Fibonacci correlation and a putative link for structure–activity relationships

Abstract

The fact that non-antibiotics can sensitise microorganisms for antibiotic treatment suggests that these molecules have valuable potential to treat multiple drug resistance. Here, we explore the spatial interaction of selected therapeutic phenothiazine hydrochloride derivatives (PTH) with various lipids. Micro-gravimetric titrations were performed on aqueous suspensions of promethazine (PMTZ), promazine (PMZ), triflupromazine (TFM), chlorpromazine (CPZ), prochlorperazine·HCl (PClP·HCl), trifluoperazine·HCl (TFP·HCl), prochlorperazine·2HC1 (PClP·2HCl), trifluoperazine·2HCl (TFP·2HCl) and synthetic 1,2diacyl-sn-glycero-3-phospholipids (PL) with even-numbered symmetric saturated diacyl chains with the headgroups choline (PC), glycerol (PG), serine (PS), ethanolamine (PE), phosphatidic acid (PA). We observed water soluble products with replicable molar ratios (MR) that could be divided into two series. ‘Series 1’ (PMTZ < PMZ < CPZ < PClP < TFP) followed the ionization potential and concomitant sedative effects. ‘Series 2’ followed the lipophilicity of PL and could be related to various non-neuronal physiological aspects. The MR of Series 2 followed the PL order PC < PG < PS < PE < PA, echoing the changes in the membrane proportions found in eukaryotic cells proceeding from the plasma membrane to the endoplasmic reticulum. The same order was found when hydrogen ion concentration was increased [Δ_iH⁺] when plotted against the MR for each separate diacyl series. The [Δ_iH⁺] of the PTH/PL was always larger than that of the self-associated pure PTH. In summary, the reproducibility and similarity of the measurements using different PTH derivatives and PL suggests that similar adducts are formed in all the cases. We propose that the PTH·PL adduct has a “helical shape” showing Fibonacci properties for molecules. These observations may open new opportunities for the development of novel therapies.