Design, Microwave-Assisted Synthesis and Druglikeness Evaluation of Two Chloroquine-Based Hybrids for Improved Resistance Profiles Against Malaria

Malaria primarily affects children and pregnant women due to pregnancy-related immune suppression. Chloroquine-based chemotherapy, if potent, could be an ideal solution given chloroquine’s pharmacokinetics that allow placental penetration in Pregnancy Associated Malaria (PAM) for example. Here, we report the design, synthesis and druglikeness evaluation of chloroquine hybrids, CQF1 and CQF64 as potential dual-acting antiplasmodial agents with improved resistance profiles. Docking studies were done on MOE v2019.01 against plasmepsin II (PDB: 1LEE) and Pf80s (PDB:5UMD). Chloroquine freebase from diphosphate was combined with triethylamine and tryptamine or 2-(chlorocarbonyl)phenyl acetate at 0⁰C, microwave irradiated for 40 and 100 seconds respectively, and crude products triturated. Elucidation was by NMR, PDA-LC/MS, FTIR, etc. Molecular descriptors/predictions were from SwissADME, ADMETlab_3.0 and ToxAlerts webservers. CQF64 showed a H-bonding interaction with Ser37 of Pl_II, and two pi-H interactions with Lys52 and Try53 of Pf80s. S-scores_(Pl_II) = -8.4333 & -7.8324 kcal/mol and S-scores_(80s) = -7.4578 & -7.0080 kcal/mol for CQF1 and CQF64 respectively. From these, predictive lipophilic ligand efficiency (pLLE) scores of 1.87 & 1.91 were computed. With the goal being to achieve balance between dual-functionality and druglikeness, these values are decent for hybrids. Spectral data were consistent with expected structures of the indole-based CQF1 (60.3% yield) and phenylacetate-based CQF64 (40.3%). Both were Ro5-compliant with 1 violation (cLogP) each. Quantitative Estimation of Druglikeness (QED) outrightly assessed CQF1 (0.411) as better than CQF64 (0.263), perhaps due to structural alerts. However, CQF64 having a lower lipophilicity (XLogP3 = 5.51) compared to CQF1 (6.07), lower melting point (67-72 vs 128-132⁰C), and lower estimated aqueous solubility (LogS = -5.86 vs -6.05), may be considered more viable. Pending biological validation and optimisation, our findings suggest that CQF64 could give a useful dual-acting antiplasmodial agent.