Synthesis and synergistic antimycobacterial screening of chlorpromazine and its metabolites

Kigondu, Elizabeth; Njoroge, Mathew; Singh, K. Chandramani; Njuguna, Nicholas M.; Warner, Digby F.; Chibale, Kelly

doi:10.1039/c3md00387f

Cited by 20 publications

(14 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As revealed by the intermediates analysis, conversion rate of the probe compound as well as type and production rates of the intermediates varied upon UV(A) and visible light irradiation in presence and absence of the photocatalyst. Three main detected products in photolysis upon UV(A) irradiation, having m/z values of 335, 317, and 301 were also reported for this reaction in similar analytical studies and for each of these compounds, one or more possible structures have been proposed [43,44,54,55]. Some of the intermediates with significant signal intensities detected throughout the photocatalytic and photolytic conversion of chlorpromazine under aerobic conditions, their retention times, masses, and reported structures are gathered in Table 1.…”

Section: Photocatalytic and Photolytic Conversion Of Chlorpromazinementioning

confidence: 63%

“…The molecular mass of the highly persistent intermediate giving the highest signal intensity with m/z value of 335 corresponds either to chlorpromazine sulfoxide (SFX) or to chlorpromazine -N-oxide [54]. Therefore, in order to identify this produced metabolite, a pure commercial SFX was analyzed by HPLC-MS and the obtained signal for the commercial SFX matched 100% to that of the metabolite with m/z value of 335 in the experimental runs, confirming the identity of the produced metabolite to be the SFX.…”

Section: Photocatalytic and Photolytic Conversion Of Chlorpromazinementioning

confidence: 99%

“…They determined the molecular structures of the three main photolysis products having m/z values of 301, 317, and 335, through an analysis by high performance liquid chromatography coupled to multiple stage mass-spectrometry (HPLC-MS n ) [43]. In another study, Kigondu et al evaluated the antimycobacterial activities of chlorpromazine and its metabolites alone and in combination with antitubercular drugs in which intermediates with m/z values of 335 and 351 were detected [54]. These compounds were also reported in an analytical study by Boehme and Strobel in which two HPLC methods have been introduced to analyze the in vitro metabolism of chlorpromazine [55].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Light-Induced Reactions of Chlorpromazine in the Presence of a Heterogeneous Photocatalyst: Formation of a Long-Lasting Sulfoxide

et al. 2019

View full text Add to dashboard Cite

A commercial carbon-modified titanium dioxide, KRONOClean 7000, was applied as a UV(A) and visible-light active photocatalyst to investigate the conversion of the antipsychotic pharmaceutical chlorpromazine in aqueous phase employing two monochromatic light sources emitting at wavelengths of 365 and 455 nm. Photocatalytic and photolytic conversion of chlorpromazine under both anaerobic and aerobic conditions was analyzed using a HPLC-MS technique. Depending on the irradiation wavelength and presence of oxygen, varying conversion rates and intermediates revealing different reaction pathways were observed. Upon visible light irradiation under aerobic conditions, chlorpromazine was only converted in the presence of the photocatalyst. No photocatalytic conversion of this compound under anaerobic conditions upon visible light irradiation was observed. Upon UV(A) irradiation, chlorpromazine was successfully converted into its metabolites in both presence and absence of the photocatalyst. Most importantly, chlorpromazine sulfoxide, a very persistent metabolite of chlorpromazine, was produced throughout the photolytic and photocatalytic conversions of chlorpromazine under aerobic conditions. Chlorpromazine sulfoxide was found to be highly stable under visible light irradiation even in the presence of the photocatalyst. Heterogeneous photocatalysis under UV(A) irradiation resulted in a slow decrease of the sulfoxide concentration, however, the required irradiation time for its complete removal was found to be much longer compared to the removal of chlorpromazine at the same initial concentration.

show abstract

Section: Photocatalytic and Photolytic Conversion Of Chlorpromazinementioning

confidence: 63%

Section: Photocatalytic and Photolytic Conversion Of Chlorpromazinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Light-Induced Reactions of Chlorpromazine in the Presence of a Heterogeneous Photocatalyst: Formation of a Long-Lasting Sulfoxide

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Concerning the amikacin-resistant strain, the resistance was reduced by four-fold with chlorpromazine. Kigondu et al ( 2014 ) have recently reported that combinations between chlorpromazine and aminoglycosides results in synergic activity against Mycobacterium smegmatis . In this study, verapamil was the efflux inhibitor that demonstrated stronger activity against these strains which are in accordance with previous reports (Rodrigues et al, 2009 , 2011 , 2012 ; Louw et al, 2011 ; Machado et al, 2012 ; Gupta et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

et al. 2015

View full text Add to dashboard Cite

Drug resistant tuberculosis continues to increase and new approaches for its treatment are necessary. The identification of M. tuberculosis clinical isolates presenting efflux as part of their resistant phenotype has a major impact in tuberculosis treatment. In this work, we used a checkerboard procedure combined with the tetrazolium microplate-based assay (TEMA) to study single combinations between antituberculosis drugs and efflux inhibitors (EIs) against multidrug resistant M. tuberculosis clinical isolates using the fully susceptible strain H37Rv as reference. Efflux activity was studied on a real-time basis by a fluorometric method that uses ethidium bromide as efflux substrate. Quantification of efflux pump genes mRNA transcriptional levels were performed by RT-qPCR. The fractional inhibitory concentrations (FIC) indicated synergistic activity for the interactions between isoniazid, rifampicin, amikacin, ofloxacin, and ethidium bromide plus the EIs verapamil, thioridazine and chlorpromazine. The FICs ranged from 0.25, indicating a four-fold reduction on the MICs, to 0.015, 64-fold reduction. The detection of active efflux by real-time fluorometry showed that all strains presented intrinsic efflux activity that contributes to the overall resistance which can be inhibited in the presence of the EIs. The quantification of the mRNA levels of the most important efflux pump genes on these strains shows that they are intrinsically predisposed to expel toxic compounds as the exposure to subinhibitory concentrations of antibiotics were not necessary to increase the pump mRNA levels when compared with the non-exposed counterpart. The results obtained in this study confirm that the intrinsic efflux activity contributes to the overall resistance in multidrug resistant clinical isolates of M. tuberculosis and that the inhibition of efflux pumps by the EIs can enhance the clinical effect of antibiotics that are their substrates.

show abstract

“…The polycyclic ring structure, which is important for the neurological action of the class, contributes to the lipophilicity of the compound and can be substituted with various groups on C-2. Chlorpromazine, another neuroleptic with efflux inhibitory properties, was tested along with its metabolites against M. smegmatis and exhibited synergistic activity when administered in combination with known antituberculosis drugs (Kigondu et al, 2014a , b ). Also chlorpromazine, that is structurally related to thioridazine, shows a violation of the Lipinsky's “rule of five” with its ClogP (5.03).…”

Section: Medicinal Chemistry For Antituberculosis Drugs: Mind the Fatmentioning

confidence: 99%

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

et al. 2018

View full text Add to dashboard Cite

The emergence of multi- and extensively drug resistant tuberculosis worldwide poses a great threat to human health and highlight the need to discover and develop new, effective and inexpensive antituberculosis agents. High-throughput screening assays against well-validated drug targets and structure based drug design have been employed to discover new lead compounds. However, the great majority fail to demonstrate any antimycobacterial activity when tested against Mycobacterium tuberculosis in whole-cell screening assays. This is mainly due to some of the intrinsic properties of the bacilli, such as the extremely low permeability of its cell wall, slow growth, drug resistance, drug tolerance, and persistence. In this sense, understanding the pathways involved in M. tuberculosis drug tolerance, persistence, and pathogenesis, may reveal new approaches for drug development. Moreover, the need for compounds presenting a novel mode of action is of utmost importance due to the emergence of resistance not only to the currently used antituberculosis agents, but also to those in the pipeline. Cheminformatics studies have shown that drugs endowed with antituberculosis activity have the peculiarity of being more lipophilic than many other antibacterials, likely because this leads to improved cell penetration through the extremely waxy mycobacterial cell wall. Moreover, the interaction of the lipophilic moiety with the membrane alters its stability and functional integrity due to the disruption of the proton motive force, resulting in cell death. When a ligand-based medicinal chemistry campaign is ongoing, it is always difficult to predict whether a chemical modification or a functional group would be suitable for improving the activity. Nevertheless, in the “instruction manual” of medicinal chemists, certain functional groups or certain physicochemical characteristics (i.e., high lipophilicity) are considered red flags to look out for in order to safeguard drug-likeness and avoid attritions in the drug discovery process. In this review, we describe how antituberculosis compounds challenge established rules such as the Lipinski's “rule of five” and how medicinal chemistry for antituberculosis compounds must be thought beyond such dogmatic schemes.

show abstract

Synthesis and synergistic antimycobacterial screening of chlorpromazine and its metabolites

Abstract: Chlorpromazine (CPZ) metabolites naturally generated in vivo were synthesized via a non-classical Polonovski reaction. CPZ and the synthesized metabolites exhibited clear synergy when tested in combination with a number of antituberculosis drugs.

Cited by 20 publications

References 30 publications

Light-Induced Reactions of Chlorpromazine in the Presence of a Heterogeneous Photocatalyst: Formation of a Long-Lasting Sulfoxide

Light-Induced Reactions of Chlorpromazine in the Presence of a Heterogeneous Photocatalyst: Formation of a Long-Lasting Sulfoxide

Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

Contact Info

Product

Resources

About