Photocatalytic Unsymmetrical Coupling of 2-Substituted Quinolines: Synthesis and Evaluation of the Antiplasmodial Potential of β-Norbenzomorphan Frameworks

Abstract

We herein report unsymmetrical coupling of 2-methylquinolines under the blue LED light conditions using iridium-based photocatalyst. This methodology represents the direct synthetic method for the β-norbenzomorphan skeleton from the quinoline moiety. The current method is more ecofriendly and efficient compared to the existing methods as manifested by green metrics parameters. Substituted quinolines gave the desired products with good to excellent yields. In vitro study of isolated compounds against the growth of Plasmodium falciparum grown in human red blood cells using SYBR green microtiter plate-based screening showed 2d (chlorine-substituted imitate) and 2o (CO2Et-substituted imitate) to have sub-micromolar IC50s against chloroquine-resistant PfINDO strain. In silico docking scores for binding to falcipain-2 were comparable (2d) or better (2o) than chloroquine.

Identification and characterization of GAP50 binders with the goal to identify novel antimalarials

“…Pathogen and Pandemic box compounds dissolved in DMSO at 10 mM were obtained from MMV. Azepino quinolines 21 and molecules from Cissampelos pareira 22 (Hayatinine, Curine and Magnocurarine) were from Dr. Upendra Sharma, IHBT, India. The sources of these drug-like molecules were: Bedaquiline (MMV689758) or HY-14881/CS-2921 (Med Chem Express), Me oquine or M2319 and Bitertanol or 45349 (Sigma), Pentamidine or 20679 (Cayman chemicals), Suramin or 1874-250 (Bio vision), and MMV688771 or S14135SC (May bridge).…”

“…A total of 951 different compounds from diverse chemical libraries [pathogen box (400), pandemic box (400), Azepino quinolines and quinolines with β benzomorphan framework 21 (140), and secondary metabolites puri ed from C. pareira 22 (11)] were screened (Fig. 1a) for (a) in silico interactions with PfGAP50 via Schrödinger drug discovery suite (version 2019-3), and (b) ability to in uence the melting temperature of GAP50 using differential scanning uorimetry (DSF).…”

“…To achieve our goal, we screened diverse compounds coming from MMV (pathogen, and pandemic box) as also laboratory synthesized quinolines (Supplementary Table 1) 21 and some phytometabolites isolated in our laboratory (Supplementary Fig 1) 21,22 against PfGAP50. Successive compound screenings which started with initial permissive cutoffs used in diverse in silico and wet lab binding assays were followed by more stringent in vitro inner membrane complex disruption microscopic assays, in vitroP.…”

Glideosomal GAP50 binders that inhibit invasion and restrict malaria parasite in vitro and in vivo

“…Pathogen and Pandemic box compounds dissolved in DMSO at 10 mM were obtained from MMV. Azepino quinolines 31 and molecules from Cissampelos pareira 32 (Hayatinine, Curine and Magnocurarine) were from Dr. Upendra Sharma, IHBT, India. The sources of these drug-like molecules were: Bedaquiline (MMV689758) or HY-14881/CS-2921 (Med Chem Express), Me oquine or M2319 and Bitertanol or 45349 (Sigma), Pentamidine or 20679 (Cayman chemicals), Suramin or 1874-250 (Bio vision), and MMV688771 or S14135SC (May bridge).…”

Glideosomal GAP50 binders that inhibit invasion and restrict malaria parasite in vitro and in vivo

“…Azepino quinolines 31 and molecules from Cissampelos pareira 32 (Hayatinine, Curine and Magnocurarine) were from Dr. Upendra Sharma, IHBT, India. The sources of these drug-like molecules were: Bedaquiline Binding nity determination using surface plasmon PfGAP50 (50 µg/ml) was immobilized on a CM5 chip in acetate buffer, pH 4.5 using EDC-NHS coupling.…”