Background: A dramatic increase in multiple-drug-resistant (MDR) Gram-positive pathogens has occurred in recent times, leading to increased rates or morbidity and mortality and also associated with high costs for the treatment of these infections. It is clear that there is an urgent need for the development of effective antimicrobial agents. The anti-bacterial activity of seven 2,2,6,6-tetramethylpiperidine (TMP)-substituted phenazines, compared to clofazimine (B663), were tested against 70 clinical isolates of methicillin-resistant Staphylococcus aureus, MDR Streptococcus pneumoniae and resistant Enterococcus sp. Methods: Standard minimum inhibitory concentration agar dilution susceptibility tests were done on all isolates, including ATCC control strains. Results: All the TMP-substituted phenazines were more active than clofazimine against all isolates tested. Compound B4125 was the most active by inhibiting all growth of the organisms tested, including vancomycin-resistant Enterococcus faecium. Conclusion: Clofazimine has been shown to have anti-staphylococcal activity. We demonstrate enhanced anti-bacterial activity of TMP-substituted phenazines against drug-resistant Gram-positive organisms compared to clofazimine.

01 Aug 2001·Investigational New DrugsQ3 · MEDICINE

Tetramethylpiperidine-Substituted Phenazines Inhibit the Proliferation of Intrinsically Multidrug Resistant Carcinoma Cell Lines

Q3 · MEDICINE

Article

Author: Constance E. J. Van Rensburg ; John F. O'sullivan ; Esme Van Niekerk ; Gisela K. Joone

The effects of nine new tetramethylpiperidine (TMP)-substituted phenazines on the growth of a human esophageal cancer cell line (WHCO3), two human hepatocellular carcinoma cell lines (PLC and HepG2) and three human colon cancer cell lines (CaCo2, COLO 320DM and HT29) were compared to those of clofazimine, B669 and five standard chemotherapeutic agents. The three most active TMP-substituted phenazines against these cell lines were B3962, B4126 and B4125 with mean IC50 values for all the cancer cell lines tested of 0.36, 0.47 and 0.48 microg/ml respectively. B3962 and B4126, but not B4125 were also the most active against a semi-continuous human fibroblast culture (MRC5). The compound with the highest tumor specificity relative to the fibroblast culture, was B4125. Importantly, there was minimal variation in sensitivity of the different cell lines, including a multidrug resistant cell line (COLO 320DM) expressing high levels of P-glycoprotein, to the TMP-substituted phenazines. This was not the case with the standard chemotherapeutic agents. The efficacy of compounds such as B4125 against a broad spectrum of multidrug resistant cancer cell lines, together with their relatively high tumor specificity, suggests that these agents may be useful in the treatment of intrinsically resistant cancers such as colon and liver cancer.

01 Jun 2000·Drug Development Research

Tetramethylpiperidine-substituted phenazines as novel anti-plasmodial agents

Author: Ronald Anderson ; John F. O'Sullivan ; Constance E.J. van Rensburg ; Nicolene Cornelius ; Marema E. Makgatho ; Janet A. Freese ; Timothy J. Egan

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-tetra methylpiper-4-ylimino)phenazine] (1-8μM), were evaluated for activity against chloroquine-, quinine-, and sulfadoxine/pyrimethamine-sensitive and -resistant strains of Plasmodium falciparum in vitro, as well as for their effects on polymerization of heme 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 chloroquine or mefloquine.Inhibition of the growth of P. falciparum was associated with interference with heme polymerization 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 chloroquine.The data presented in this study demonstrate that the TMP-substitution at position 2 on the phenazine nucleus of riminophenazines confers antiplasmodial activity on these compoundsThese may prove to be useful forerunners in the design of novel anti-plasmodial pharmacol. agents.

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria, Falciparum	Discovery	South Africa	University of Pretoria	-

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