Microwave-assisted Synthesis and Virtual Evaluation of 2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methyl 2-fluorobenzoate: an O-linked mefloquine ester and its ether equivalent

Hybrid antimalarial drugs may delay the development of Plasmodial resistance. Two of our previously reported antiplasmodial fragments F56 (2-fluorobenzoyl chloride) and F67 (2-fluorobenzylchloride) were here coupled to mefloquine and evaluated as potentially usable hybrids. Mefloquine hydrochloride was basified to obtain the (±)-erythro freebase (MFQ), and the amine was boc-protected (BMB). This was combined with F56 under microwave irradiation to yield the ester. F67 was also coupled to BMB under reflux to give the ether. Products were obtained as hydrochloride salts – doubling as a deprotection step – after purification by flash chromatography. Mass spectroscopy (MS), liquid chromatography (LC), and UV-Vis spectroscopy were done on a PDA-LC/MS system. NMR spectra were obtained at 600 MHz. Molecular descriptors were computed on the ADMETLab3.0 and SwissADME webservers. Spectral data were consistent with the expected structures of both O-linked hybrids. The microwave irradiated ester product, MBF56B had a surprisingly lower yield (27.73%) than the ether MBF67B (44.3%). Both products showed LC Rt_{major =} 13.09 and 13.59 mins respectively, with respective possible diastereomer products at Rt_minor = 16.67 and 14.47 mins. Both compounds were Rule-of-five (Ro5)-compliant with Quantitative Estimation of Druglikeness (QED) scores, 0.33 and 0.40 respectively. Both showed drop-offs in predicted CYP3A4 inhibition. The ester showed improvements in clearance while the ether suggested improved metabolic stability. We successfully synthesised these two mefloquine hybrids, with the ether slightly better overall. Their medicinal chemistry indices intimate the success of this fragment-plus-drug approach in developing relatively drug-like hybrids that could, on bio-evaluation, be useful dual-acting antimalarial agents - tackling resistance.