Accepted Manuscript New Developments in Antiinfectives Research for Tropical Infectious Diseases Kelly Chibale PII: DOI: Reference:
S0968-0896(15)00393-4 http://dx.doi.org/10.1016/j.bmc.2015.04.077 BMC 12289
To appear in:
Bioorganic & Medicinal Chemistry
Please cite this article as: Chibale, K., New Developments in Antiinfectives Research for Tropical Infectious Diseases, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.04.077
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: New Developments in Antiinfectives Research for Tropical Infectious Diseases Guest Editor: Kelly Chibale
Diseases caused by infectious agents are responsible for unacceptably high levels of morbidity and mortality especially in developing countries of Africa, South America, and Asia. A crippling infectious disease burden continues to choke economic growth on these continents. While antiinfective drug discovery and development had been stagnant for decades, there has been a renewed global effort to tackle the infectious disease burden with the involvement of large pharmaceutical companies in precompetitive drug discovery via public−private consortia along with biotechs, and not-for-profit organizations. In particular networks of partnerships involving industry and academia, with a mentoring component, coordinated by not-for-profit virtual R&D organizations have played a significant role in advancing antiinfective drug discovery and development for tropical infectious diseases. This has resulted in an increasing collaborative landscape on globally aligned programmes and establishment of centres of excellence. New tools and technologies are also increasingly being brought to bear on drug discovery against tropical infectious diseases.
Through this Symposia-In-Print (albeit not an exhaustive treatise), some of the more recent efforts in antiinfective drug discovery from both industry and academia will be highlighted. The focus is on tropical infectious diseases. Specifically this Symposia-In-Print will focus on recent developments in the discovery of novel antiparasitic and antimycobacterial agents stemming from analog-based design, target-based and phenotypic whole cell screening approaches. In terms of therapeutic areas, the scope of the Symposia-In-Print is limited to malaria, tuberculosis, Human African trypanosomiasis, Leishmaniasis, Schistosomiasis and Human trichomoniasis.
The first manuscript, a perspective authored by Ujjini H. Manjunatha and Paul W. Smith from the Novartis Institute for Tropical Diseases (NITD) is an excellent example of a public-private partnership involving the global healthcare company Novartis and the Singapore Economic Development Board targeting tropical infectious diseases. Manjunatha and Smith describe their experiences and provide insights gained from their molecular target- and cell-based TB drug discovery efforts with particular emphasis on medicinal chemistry optimisation of hits from phenotypic whole cell high-throughput screening. Within the context of analog-based drug discovery, two timely reviews are devoted to the concept of hybrid molecules in malaria as a strategy to overcome and/or slow down the emergence of resistant malaria parasite strains. One review by Matthias D'hooghe and colleagues focuses on quinoline-containing hybrid compounds wherein two biologically active molecules are conjugated into one. On the other hand Francisca Lopes and colleagues not only focus on hybrid antimalarials but also offer insight into how the hybrid strategy has been exploited as a rational targeted system of delivering agents with different mechanisms of action against either a single target or different targets involved in the different stages of the parasite's life-cycle. This has been made possible by new tools and technologies that facilitate the targeting of the parasite life-cycle stages. Selectively targeting the parasite life cycle stages is also ably demonstrated by Lyn-Marie Birkholtz and colleagues in the article that follows. The public disclosure of data from phenotypic whole cell high throughput screening (HTS) campaigns has provided an opportunity to access novel antimalarial scaffolds. Coupled with knowledge of existing parasite and human targets, this has allowed the exploitation of the whole cell scaffolds in the appropriate target context. This is demonstrated by Marvin Meyers and colleagues in their article on the spiropiperidine hydantoin class of antimalarials, which was identified from the GlaxoSmithKline Tres Cantos Anti-Malaria Set (TCAMS) and is similar to known aspartic protease inhibitors. .
Several authors highlight the usefulness of repurposing and/or repositioning molecular targets and chemotypes for new therapeutic uses. At the target level, the article by Kip Guy and colleagues present data on the potential development of human histone deacetylase inhibitors (HDACi) with appropriate specificity and potency against Trypanosoma brucei brucei, the causative agent of Human African trypanosomiasis. At the chemotype level, the groups of Diego Muñoz Torrero and Biot respectively utilize compounds and clinical candidates based on the 4-aminoquinoline template against Trypanosoma brucei spp while Jennifer Keiser and colleagues utilize compounds containing a peroxide warhead found in the antimalarial drug artemisinin against Schistosoma mansoni. Articles by Karl Werbovetz and colleagues on antileishmanial quinazolines as well as Vipan Kumar and colleagues on anti-Trichomonas vaginalis isatins provide additional examples of chemotypes that are being repositioned. The penultimate article by Timothy Egan and colleagues ably demonstrates how HTS and structure-activity relationship data can be mined and combined with Bayesian statistics to derive optimized activity models for predicting beta-haematin target inhibition and whole cell antiplasmodial activities. This transitions nicely into the last manuscript by John Overington and colleagues where attention is focused on a computational analysis of the relationship between target-class and physicochemical properties of antibacterial drugs. This analysis by Overington and colleagues provides a reality check on the widely held view that the poor success rate for antibacterials from screening approaches is due to the chemical space properties of screening collections. I sincerely hope that this special issue will contribute to attracting researchers to the field of drug discovery against tropical infectious diseases. Finally I would like to thank Prof Herbert Waldmann for inviting me to be the Guest Editor for this SIP.
Kelly Chibale Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; E-mail: [email protected].
S0968-0896(15)00393-4 http://dx.doi.org/10.1016/j.bmc.2015.04.077 BMC 12289
To appear in:
Bioorganic & Medicinal Chemistry
Please cite this article as: Chibale, K., New Developments in Antiinfectives Research for Tropical Infectious Diseases, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.04.077
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: New Developments in Antiinfectives Research for Tropical Infectious Diseases Guest Editor: Kelly Chibale
Diseases caused by infectious agents are responsible for unacceptably high levels of morbidity and mortality especially in developing countries of Africa, South America, and Asia. A crippling infectious disease burden continues to choke economic growth on these continents. While antiinfective drug discovery and development had been stagnant for decades, there has been a renewed global effort to tackle the infectious disease burden with the involvement of large pharmaceutical companies in precompetitive drug discovery via public−private consortia along with biotechs, and not-for-profit organizations. In particular networks of partnerships involving industry and academia, with a mentoring component, coordinated by not-for-profit virtual R&D organizations have played a significant role in advancing antiinfective drug discovery and development for tropical infectious diseases. This has resulted in an increasing collaborative landscape on globally aligned programmes and establishment of centres of excellence. New tools and technologies are also increasingly being brought to bear on drug discovery against tropical infectious diseases.
Through this Symposia-In-Print (albeit not an exhaustive treatise), some of the more recent efforts in antiinfective drug discovery from both industry and academia will be highlighted. The focus is on tropical infectious diseases. Specifically this Symposia-In-Print will focus on recent developments in the discovery of novel antiparasitic and antimycobacterial agents stemming from analog-based design, target-based and phenotypic whole cell screening approaches. In terms of therapeutic areas, the scope of the Symposia-In-Print is limited to malaria, tuberculosis, Human African trypanosomiasis, Leishmaniasis, Schistosomiasis and Human trichomoniasis.
The first manuscript, a perspective authored by Ujjini H. Manjunatha and Paul W. Smith from the Novartis Institute for Tropical Diseases (NITD) is an excellent example of a public-private partnership involving the global healthcare company Novartis and the Singapore Economic Development Board targeting tropical infectious diseases. Manjunatha and Smith describe their experiences and provide insights gained from their molecular target- and cell-based TB drug discovery efforts with particular emphasis on medicinal chemistry optimisation of hits from phenotypic whole cell high-throughput screening. Within the context of analog-based drug discovery, two timely reviews are devoted to the concept of hybrid molecules in malaria as a strategy to overcome and/or slow down the emergence of resistant malaria parasite strains. One review by Matthias D'hooghe and colleagues focuses on quinoline-containing hybrid compounds wherein two biologically active molecules are conjugated into one. On the other hand Francisca Lopes and colleagues not only focus on hybrid antimalarials but also offer insight into how the hybrid strategy has been exploited as a rational targeted system of delivering agents with different mechanisms of action against either a single target or different targets involved in the different stages of the parasite's life-cycle. This has been made possible by new tools and technologies that facilitate the targeting of the parasite life-cycle stages. Selectively targeting the parasite life cycle stages is also ably demonstrated by Lyn-Marie Birkholtz and colleagues in the article that follows. The public disclosure of data from phenotypic whole cell high throughput screening (HTS) campaigns has provided an opportunity to access novel antimalarial scaffolds. Coupled with knowledge of existing parasite and human targets, this has allowed the exploitation of the whole cell scaffolds in the appropriate target context. This is demonstrated by Marvin Meyers and colleagues in their article on the spiropiperidine hydantoin class of antimalarials, which was identified from the GlaxoSmithKline Tres Cantos Anti-Malaria Set (TCAMS) and is similar to known aspartic protease inhibitors. .
Several authors highlight the usefulness of repurposing and/or repositioning molecular targets and chemotypes for new therapeutic uses. At the target level, the article by Kip Guy and colleagues present data on the potential development of human histone deacetylase inhibitors (HDACi) with appropriate specificity and potency against Trypanosoma brucei brucei, the causative agent of Human African trypanosomiasis. At the chemotype level, the groups of Diego Muñoz Torrero and Biot respectively utilize compounds and clinical candidates based on the 4-aminoquinoline template against Trypanosoma brucei spp while Jennifer Keiser and colleagues utilize compounds containing a peroxide warhead found in the antimalarial drug artemisinin against Schistosoma mansoni. Articles by Karl Werbovetz and colleagues on antileishmanial quinazolines as well as Vipan Kumar and colleagues on anti-Trichomonas vaginalis isatins provide additional examples of chemotypes that are being repositioned. The penultimate article by Timothy Egan and colleagues ably demonstrates how HTS and structure-activity relationship data can be mined and combined with Bayesian statistics to derive optimized activity models for predicting beta-haematin target inhibition and whole cell antiplasmodial activities. This transitions nicely into the last manuscript by John Overington and colleagues where attention is focused on a computational analysis of the relationship between target-class and physicochemical properties of antibacterial drugs. This analysis by Overington and colleagues provides a reality check on the widely held view that the poor success rate for antibacterials from screening approaches is due to the chemical space properties of screening collections. I sincerely hope that this special issue will contribute to attracting researchers to the field of drug discovery against tropical infectious diseases. Finally I would like to thank Prof Herbert Waldmann for inviting me to be the Guest Editor for this SIP.
Kelly Chibale Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; E-mail: [email protected].
