Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains

Abstract

Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria.

Quinolizidine-Derived Lucanthone and Amitriptyline Analogues Endowed with Potent Antileishmanial Activity

“…Thus, when pursuing our investigation on antiplasmodial [27][28][29] and antileishmanial [30,31] agents we deemed worthwhile the study of the antileishmanial activity of a set of lucanthone analogues with a modified substitution pattern, and of a few compounds embodying the diarylethene substructure of, e.g., chlorprothixene, amitriptyline and cyclobenzaprine. The studied compounds were characterized by the presence of the bulky quinolizidinylalkyl moieties, which were shown to improve the antiplasmodial and/or antileishmanial activity in the corresponding chloroquine and clofazimine analogs [30] and also in the set of 1-basic substituted 2-phenyl/benzyl benzimidazoles [31].…”

Investigations of an annulation-fragmentation-spirocyclisation approach to fawcettimine-type Lycopodium alkaloids

“…18 More recently, chemists at Millenium Pharmaceuticals employed a formal ortho-quinone methide cycloaddition of the same enamine in a synthesis of an HIVrelevant CCR5 antagonist. 19 Beyond these examples, synthetic transformations in the majority of the rest of the ~80 publications mentioning such species are limited to simple additions to, or reductions of, the iminiums A. With this background, initial studies focused on optimising the preparation of enamine 10 and surveying its alkylation chemistry with functionalised electrophiles.…”

“…Rf 0.45 (ether); νmax (thin film)/cm -1 2930m, 1678s, 1448m, 1321m, 1116m; δH (500 MHz, CD2Cl2) 1.40−1.54 (4 H, m), 1.57−1.71 (2 H, m), 1.85 (1 H, dt, J 13.5, 6.0), 1.87−1.96 (2 H, m), 2.07−2. 19 (2 H, m), 2.25 (1 H, ddd, J 13.5, 8.5, 6.0), 2.84 (1 H, dd, J 13.5, 1.5), 2.88 (1 H, ddt, J 13.5, 5.0, 1.5), 3.15 (1 H, dddd, J 12.5, 7.5 , 4.0, 1.0), 3.33 (1 H, dddd, J 12.5, 8.5, 3.5, 1.0), 3.79−3.90 (5 H, m); δC (125 MHz, CD2Cl2) 22.6, 27.9, 35.3, 37.9, 43.6, 43.9, 45.7, 48.0, 54.9, 64.6, 64.9, 117.1, 185.2 (one resonance obscured by solvent peak); HRMS (ESI + ) found 274.1414, C14H21NNaO3 (MNa + ) requires 274.1414. [1,3]dioxolane] (29) p-TsOH•H2O (34.9 mg, 0.184 mmol) was added to a solution of ketone 9 (30.0 mg, 0.167 mmol) and ethylene glycol (18.6 μL, 0.334 mmol) in benzene (2.7 mL) and the mixture was stirred under reflux for 16 h. Satd.…”

“…Rf 0.50 (1:1 petrol:ether); νmax (thin film)/cm -1 2918w, 1715s, 1483m, 1312m, 1119s, 1018m; δH (500 MHz, CD2Cl2) 1.90 (2 H, quin, J 6.5), 1.95 (2 H, quin, J 6.5), 2. 19 (2 H, t, J 6.5), 2.24 (2 H, t, J 6.5), 2.51 (2 H, s), 2.52 (2 H, s), 3.14 (2 H, t, J 6.5), 3.17 (2 H, t, J 6.5), 3…”

Ultrasonic Synthesis and Preliminary Evaluation of Anticoronaviral Activity of 6,7-Dimethoxy-4-(4-(4-methoxyphenyl)piperazin-1-yl)-1-methylquinolin-1-ium Iodide

“…Both compounds are available as therapeutics for treatment malaria [1], rheumatoid arthritis [2], lupus [3], porphyria cutanea tarda [4]. Decreased antimalarial efficacy of chloroquine over time, its high toxicity during long-term use, the lower antiparasitic activity of hydroxychloroquine, the side effects caused by both drugs, as well as the new discovered applications of them [5,6], are the main reasons to develop novel synthetic routes to modify their structures in less toxic analogues bearing better pharmacokinetic properties [7][8][9][10][11]. Since the promising in vitro efficacy of chloroquine and hydroxychloroquine against SARS-CoV-2 were firstly reported by the group of Prof. Wang [12,13], the investigations of an anticoronavirus potential of both compounds and other known therapeutics, their derivatives, are the focus of a number of research studies [14][15][16][17][18].…”