Quinoline‐Dihydropyrimidin‐2(1H)‐one Hybrids: Synthesis, Biological Activity, and Mechanistic Studies

Abstract

A novel class of quinoline-dihydropyrimidin-2(1H)-one (DHPM) hybrids was synthesized and in vitro antiplasmodial activity was evaluated against chloroquine sensitive (D10) and chloroquine resistant (Dd2) strains of Plasmodium falciparum, the human malaria parasite. The antiplasmodial activity was compared to previously reported DHPM based molecular hybrids. Dual mode of antiplasmodial action of the most active member has been evaluated through heme binding study and in silico docking in the active site of dihydrofolate enzymes (wild-type as well as mutant). Favourable pharmacokinetic parameters were pre-dicted in the ADMET evaluation. The new hybrids were also tested against a number of DNA and RNA viruses. No antiviral activity was found, except for one hybrid that showed mild inhibitory activity against two strains of cytomegalovirus (AD-169 and Davis), The most active hybrid was found to be a selective inhibitor of the growth of P. falciparum as well as a modest inhibitor of varicella zoster virus in HEL cells. Cytotoxicity of all hybrids was assessed in HEL, HeLa, Vero, MDCK, and CRFK cell cultures.

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…Quinoline-dihydropyrimidin-2(1H)-ones (46, Figure 17) were reported by Parth and co-workers acting as anti-malarial agents with the lowest IC 50 against PfD10 (IC 50 of 0.514 μM) and PfDd2 (IC 50 of 0.285 μM) through binding with heme. [77] Ishmail et al have synthesized quinoline-and aminoquinoline-triazole scaffolds complexed with tricarbonyl manganese and rhenium (47-49). These compounds reported good anti-malarial activity and also studied the photodissociation properties of complexes with the release of carbon monoxide upon exposure to radiation at 365 nm.…”

Chemistry of Quinoline Based Heterocycle Scaffolds: A Comprehensive Review

“…Compound 14b(n = 3) was found to be most potent compound having anti-plasmodial activity against Dd2 CQ R strain with IC 50 value 0.285 μM as compared to CQ (IC 50 = 0.138 μM) Compounds 13(a-b) and 14(a-b) inhibited the cytomegalovirus and varicella-zoster virus, respectively. [21] Nisheeth C Desai et al developed a novel method for synthesising pharmacologically important heterocycles with thiazole and quinoline moieties bridged by 2-azetidinone ring. Vilsmeier-Haack reaction was initially used to synthesise 2-Chloroquinoline-3-carboxaldehyde derivatives 15(R = À H, À CH 3 ) followed by heating with thiosemicarbazide in the presence of methanol and stirring for 1 h at 50 °C to get 2-((2chloroquinolin-3-yl) methylene) hydrazinecarbothioamides 16 (R = À H,À CH 3 ).…”

“…It was prepared as chromogenic sensor for copper (II) and biological thiols (GSH, Cys, Hcy). For its synthesis condensation reaction was carried out between compound (20) and (21) in the presence of Methyl alcohol. Compound BQ (22) shows optical variations to Cu (II) ion as quinoline moiety act as chromophore and functional group.…”

“…These compounds were found to be non ‐toxic in HEL, HeLa, Vero and CRFK cell cultures. Compound 14b(n=3) was found to be most potent compound having anti‐plasmodial activity against Dd2 CQ R strain with IC 50 value 0.285 μM as compared to CQ (IC 50 =0.138 μM) Compounds 13(a – b) and 14(a – b) inhibited the cytomegalovirus and varicella‐zoster virus, respectively [21] …”

Direct Regioselective Hydro(hetero)arylation/Cyclocondensation Reactions of β-(2-Aminophenyl)-α,β-ynones by Means of Transition-Metal Catalysis/Brønsted Acid Synergism: Experimental Results and Computational Insights

“…We envisaged that the direct C–H functionalization of electron-rich aromatic heterocycles/arenes should bypass the need for the prefunctionalization of these starting materials, achieving more sustainable synthetic methodologies. In particular, the key role of the native heteroatom as a directing group in the regioselective C–H bond functionalization of heterocycles should allow them to enter into new classes of biologically active compounds …”