Antimalarial drugs. 60. Synthesis, antimalarial activity, and quantitative structure-activity relationships of tebuquine and a series of related 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl][1,1'-biphenyl]-2-ols and N.omega.-oxides

Abstract

A series of 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl] [1,1'-biphenyl]-2-ols and N omega-oxides was prepared from the substituted 1-phenyl-2-propanones proceeding through the 5-nitro[1,1'-biphenyl]-2-ols, the corresponding amino, and acetamido derivatives to the N-[5-[(alkylamino)methyl]-6-hydroxy[1,1'-biphenyl]-3-yl]acetamides and final condensation with 4,7-dichloroquinoline or the N-oxide. In a quantitative structure-activity relationship study first run on 28 and later expanded to 40 substituted phenyl analogues and their N omega-oxides, increasing antimalarial potency vs. Plasmodium berghei in mice was found to be correlated with decreasing size (sigma MR) and electron donation (sigma sigma) of the phenyl ring substituents. A significant correlation with N omega-oxidation could not be demonstrated. Initial high activity against P. berghei infections in mice led to expanded studies that demonstrated in addition excellent activity against resistant strains of parasite, activity in primate models, and pharmacokinetic properties apparently allowing protection against infection for extended periods of time even after oral administration. Such properties encourage the clinical trial of a member of this class in man.

Antimalarial Mannoxanes: Hybrid Antimalarial Drugs with Outstanding Oral Activity Profiles and A Potential Dual Mechanism of Action

“…15.2 (14,15,15,15,16,16) 99.8 Amodiaquine (8) 11.2 (9,11,11,12,13) 100.0 Amodiaquine + 11 [a] 8.2 (7,7,8,8,11) 87.7 Artesunate (2) 8.2 (7,8,8,9,9) 99.1…”

“…In this case, we can detect adducts generated through C-centred radical formation with subsequent alkylation of the porphyrin macrocycle at the a, b and d positions (figure S1, Supporting Information). [1a] 99.9 [1a] Artesunate 4.8 4.9 9.0 (7,7,7,10,14) 99.1 RKA182 ND 1.1 [3] Table 2. Average survival and suppression of parasitaemia of mice infected with P. berghei ANKA following oral dosing of 3 10 mg kg À1 .…”

“…The Mannich base phenol antimalarials have been known since the 1940s when optimisation of bialamicol led to non-quinoline-based molecules with potent oral activity in monkey models of malaria (6 a and 6 b). [7] Based on these early studies, amodiaquine (8) [8] and the bis-Mannich pyronaridine [9] were discovered. The presence of the Mannich base phenol unit in these compounds is critical for antimalarial activity and contributes significantly to intraparasitic accumulation and hematin binding (see below).…”

Pentafluorobenzaldehyde and its utilizing in organic synthesis

“…The PFBA reacts very easily with nitromethane and with nitroethane in condensation reactions [23,269]. After 5 h heating in the presence of ammonium acetate, nitrostyrenes (37b) are formed in high yields (Scheme 28).…”

Recent developments in the design and synthesis of hybrid molecules basedon aminoquinoline ring and their antiplasmodial evaluation

“…Subsequent research into the preparation of AQ-analogues containing side chains which were less susceptible to metabolism afforded many diverse derivatives [150], one of which was tebuquine (51, TQ), a substituted 4-N-biphenylylaminoquinoline, exhibited greater antimalarial activity than AQ in vivo and in vitro [150,151]. Mannich base biaryl moieties of molecules are synthesized via a SuzukiMiyaura cross-coupling reaction that allows molecular diversification [152].…”