Introduction

4,7-Dichloroquinoline (DCQ; Figure 1) represents a group of synthetic molecules inspired by natural products with important roles in biological and biomedical areas. 4,7-dichloroquinoline is encountered as an organic intermediate in the martufacttirc of chloroquine and other quinoline derivatives.It is a solid,handled as large chips or flakes.[1-2] 4,7-Dichloroquinoline is an important component of several antimalarial drugs 15,26 and is therefore a major driver of cost in the production of amodiaquine as it accounts for over 40% of the raw material costs.

Synthesis of 4,7-Dichloroquinoline

The process for the commercial production of 4,7-dichloroquinoline (5) was developed according to the methodology of Price and Roberts (Scheme1), which is centered on diethoxymethylene malonate (6) and meta-chloroaniline (7), with necessary modifications.The synthesis of 4,7-dichloroquinoline (5) commenced by the conjugate addition of diethoxymethylene malonate (6) and meta-chloroaniline (7) to afford the acrylate intermediate 8,which, upon thermal cyclization in diphenyl ether (DPE),afforded the quinoline ester 9 in good yields (90?96%). Hydrolysis of the ester (9) in aqueous sodium hydroxide to the showed an extra peak at a retention time of 13.13 min with asimilar mass to that of 4,7-dichloroquinoline (5).The process has the advantages of simple operation，low cost and significantly improved yield，and is more suitable for industrial production.[3]

Toxicity effect of 4,7-dichloroquinoline on A. aegypti and A. stephensi.

In agreement with the current research, Saini et al. studied the antimalarial potential of quinoline-pyrazolo pyridine derivatives. Mosquitocidal results revealed that the synthesized 4,7-dichloroquinoline was highly toxic to developmental stages of malarial and dengue vectors providing LC₅₀ values ranging from 4.408 μM/mL (larva I) to 7.958 μM/mL(pupa) for the chosen malaria vector and 5.016 μM/mL (larva I) to 10.669 μM/mL (pupa) for the dengue vector. Recently, Rueda et al. demonstrated both adulticidal and larvicidal activity of A. aegypti when exposed to synthesized α-amino nitriles. Shao et al. showed for hexahydroimidazo [1,2-α] pyridine derivativesthat they had excellent pesticidal properties against aphid species. Furthermore, Sun et al. highlighted thatpiperazinedione derivatives were highly toxic on the root-knot nematode Meloidogyne incognita. The K1 strain being resistant against chloroquine (CQ) was shown by Gayam and Ravi and that cinnamoylated chloroquine hybrid analogues showed highest antimalarial activity. Lastly, Kondaparia et al. found that 4-amino quinolines showed considerable antimalarial activity on Plasmodium falciparum. It was proposed that death rate caused by 4,7-dichloroquinoline for the diferent life stages of larval populations of both A. stephensi and A. aegypti may be due to the upregulation of electronegative ions which provided better biological activity on target pests. Indeed, Rahuman et al. reported that Zingiber of cinale derived molecules showed toxicity on the 4th larval stages of the dengue vectors belonging to Culex species.[4]

Application Research example

1.Characterization of the fragmentation mechanisms in electrospray ionization tandem mass spectrometry of chloroquinoline derivatives with larvicidal activity against Aedes aegypti.

This work aimed to characterize  4,7-dichloroquinoline and its derivatives by high-resolution electrospray ionization (ESI) mass spectrometry and tandem mass spectrometry (ESI-MS/MS), supported by theoretical calculations. Biological assays were carried out with 4,7-dichloroquinoline and its derivatives to determine LC50 values against Aedes aegypti larvae.

Five 4,7-dichloroquinoline derivatives were synthesized by using previously described protocols. ESI-MS/MS analyses were carried out with a quadrupole/time-of-flight and ion-trap instrument. The proposed gas-phase protonation sites and fragmentation were supported by density functional theory calculations. The larvicidal tests were performed with the Ae. aegypti Rockefeller strain, and the LC₅₀ values were determined by employing five test concentrations. Larval mortality was determined after treatment for 48?h.  4,7-Dichloroquinoline bromides or aldehydes (C-3 or C-8 positions), as well as the trimethylsilyl derivative (C-3 position), were prepared. Detailed ESI-MS/MS data revealed heteroatom elimination through an exception to the even-electron rule, to originate open-shell species. Computational studies were used to define the protonation sites and fragmentation pathways. High activity of  4,7-dichloroquinoline and its derivatives against Ae. aegypti larvae was demonstrated. The results provided a well-founded characterization of the fragmentation reactions of  4,7-dichloroquinoline and its derivatives, which can be useful for complementary studies of the development of a larvicidal product against Ae. aegypti.[5]

2.Synthesis of new series of quinoline derivatives with insecticidal effects on larval vectors of malaria and dengue diseases.

Mosquito borne diseases are on the rise because of their fast spread worldwide and the lack of effective treatments. Here we are focusing on the development of a novel anti-malarial and virucidal agent with biocidal effects also on its vectors. We have synthesized a new quinoline (4,7-dichloroquinoline) derivative which showed significant larvicidal and pupicidal properties against a malarial and a dengue vector and a lethal toxicity ranging from 4.408 μM/mL (first instar larvae) to 7.958 μM/mL (pupal populations) for Anopheles stephensi and 5.016 μM/mL (larva 1) to 10.669 μM/mL (pupae) for Aedes aegypti. In-vitro antiplasmodial efficacy of 4,7-dichloroquinoline revealed a significant growth inhibition of both sensitive strains of Plasmodium falciparum with IC₅₀ values of 6.7 nM (CQ-s) and 8.5 nM (CQ-r). Chloroquine IC₅₀ values, as control, were 23 nM (CQ-s), and 27.5 nM (CQ-r). In vivo antiplasmodial studies with P. falciparum infected mice showed an effect of 4,7-dichloroquinoline compared to chloroquine. The quinoline compound showed significant activity against the viral pathogen serotype 2 (DENV-2). In vitro conditions and the purified quinoline exhibited insignificant toxicity on the host system up to 100 μM/mL. Overall, 4,7-dichloroquinoline could provide a good anti-vectorial and anti-malarial agent.[4]

References

[1] Pickering FC, Ive FA. Allergic contact dermatitis from 4,7-dichloroquinoline. Contact Dermatitis. 1982;8(4):269-270. doi:10.1111/j.1600-0536.1982.tb04215.x

[2] Odhiambo OC, Wamakima HN, Magoma GN, et al. Efficacy and safety evaluation of a novel trioxaquine in the management of cerebral malaria in a mouse model. Malar J. 2017;16(1):268. Published 2017 Jul 3. doi:10.1186/s12936-017-1917-6

[3] Gohain M, Malefo MS, Kunyane P, et al. Process Development for the Manufacture of the Antimalarial Amodiaquine Dihydrochloride Dihydrate. Org Process Res Dev. 2023;28(1):124-131. Published 2023 Dec 18. doi:10.1021/acs.oprd.3c00205

[4] Murugan K, Panneerselvam C, Subramaniam J, et al. Synthesis of new series of quinoline derivatives with insecticidal effects on larval vectors of malaria and dengue diseases. Sci Rep. 2022;12(1):4765. Published 2022 Mar 19. doi:10.1038/s41598-022-08397-5

[5] da Silva RM, Barbieri JG, Murie VE, et al. Characterization of the fragmentation mechanisms in electrospray ionization tandem mass spectrometry of chloroquinoline derivatives with larvicidal activity against Aedes aegypti. Rapid Commun Mass Spectrom. 2024;38(12):e9739. doi:10.1002/rcm.9739