Tetramethylpiperidine-substituted phenazines as novel anti-plasmodial agents

Abstract

Two novel derivatives of clofazimine [3‐(p‐chloroanilino)‐10‐(p‐chlorophenyl)‐2,10‐dihydro‐2‐isopropylimino)phenazine] and the tetramethylpiperidine (TMP)‐substituted phenazines, B4119 [3‐(3‐chloro‐4‐fluoroanilino)‐10‐(3‐chloro‐4‐fluorophenyl)‐2,10‐dihydro‐2(2,2,6,6‐tetramethylpiper‐4‐ylimino)phenazine] and B4158 [3‐(4‐isopropylanilino)‐10‐(4‐isopropylphenyl)‐2,10‐dihydro‐2‐(2,2,6,6‐tetramethylpiper‐4‐ylimino)phenazine] (1–8 μM), were evaluated for activity against chloroquin‐, quinine‐, and sulfadoxine/pyrimethamine‐sensitive and ‐resistant strains of Plasmodium falciparum in vitro, as well as for their effects on polymerisation of haeme to β‐hematin. By using microscopic and flow cytometric methods, it was found that B4119 and B4158, but not clofazimine, inhibited the growth of sensitive, as well as resistant strains of P. falciparum with IC50 values between 0.22 and 0.7 μM, indicating lack of cross‐resistance. Augmentation of anti‐plasmodial activity was observed when B4119 and B4158 were used in combination with chloroquin or mefloquine. Inhibition of the growth of P. falciparum was associated with interference with haeme polymerisation to β‐hematin in vitro, while administration of B4119 to P. berghei‐infected mice was accompanied by a significant reduction in parasitemia and improved therapeutic activity was observed when this agent was combined with chloroquin. The data presented in this study demonstrate that the TMP‐substitution at position 2 on the phenazine nucleus of riminophenazines confers anti‐plasmodial activity on these compounds. These may prove to be useful forerunners in the design of novel anti‐plasmodial pharmacologic agents. Drug Dev. Res. 50:195–202, 2000. © 2000 Wiley‐Liss, Inc.

An efficient four-component domino protocol for the rapid and green synthesis of functionalized benzo[a]pyrano[2,3-c]phenazine derivatives using caffeine as a homogeneous catalyst

“…Then, in method A, 2,4-dichlorobenzaldehyde (1 mmol), malononitrile (1 mmol), and caffeine as catalyst were added, the flask was fitted with a condenser, and the resulting mixture in ethanol (10 mL) was heated to reflux under stirring. The use of different amounts of catalyst (20,25,30,35 Using these optimized reaction conditions, the scope and efficiency of the reaction were explored for the synthesis of a wide variety of substituted benzo[a]pyrano[2,3-c]phenazine derivatives. The results are summarized in Table 2.…”

“…Phenazine compounds are nitrogen-containing heterocycles that are found in natural and synthetic products [18][19][20][21][22][23][24] showing a diversity of biological functions, including antimalarial [25,26], trypanocidal [27], fungicidal [28,29], antiplatelet [30], and antitumor [31] activities. Benzo [a]phenazines that have been formed from a naphthoquinone and phenazin show high activity as dual inhibitors of topoisomerase I and II and are useful as antitumor agents [32].…”

14b-Chloro-4a-methoxy-3,3-dimethyl-2,3,4a,14b-tetrahydro-1H-benzo[a]pyrano[2,3-c]phenazine: a new active structural type againstMycobacterium tuberculosis

“…For general background, see: Agrawal et al (2007); Andradede Neto et al (2004); Bahnmü ller et al (1988); Emoto et al (2000); Franzblau et al (1998); Geiger et al (1988); Rewcastle et al (1987); Van Rensburg et al 2000; Wang et al (2000); Janin (2007); Laursen et al (2002); Mackgatho et al (2000). For related literature, see: Allen et al (1987); Cremer & Pople (1975).…”

Microwave-assisted Domino Cyclization for the Synthesis of Novel Spiro-benzo[a]phenazine Annulated Heterocycles Catalyzed by a Basic Ionic Liquid

“…13,14 The effective structure of polyheterocyclic skeletons bearing several diverse functionalities is a challenging theme in modern organic synthesis. 15,16 Among these polyheterocyclic skeletons, the various structurally different phenazines have received further interest because of their biological characteristics such as trypanocidal, 17 fungicidal, 18 antimalarial, 19 and antiplatelet 20 activities. By virtue of their DNA-accommodating ability, they represent antitumor activity in leukemia and solid tumors.…”