scholarly journals Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets

2021 ◽  
Vol 11 ◽  
Author(s):  
Sangmi Oh ◽  
Lena Trifonov ◽  
Veena D. Yadav ◽  
Clifton E. Barry ◽  
Helena I. Boshoff
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Genome Sequence ◽  
Small Molecule ◽  
Mechanism Of Action ◽  
Clinical Testing ◽  
Gene Essentiality ◽  
Structure Activity ◽  
Small Molecule Libraries ◽  
Discovery Pipeline

More than two decades have elapsed since the publication of the first genome sequence of Mycobacterium tuberculosis (Mtb) which, shortly thereafter, enabled methods to determine gene essentiality in the pathogen. Despite this, target-based approaches have not yielded drugs that have progressed to clinical testing. Whole-cell screening followed by elucidation of mechanism of action has to date been the most fruitful approach to progressing inhibitors into the tuberculosis drug discovery pipeline although target-based approaches are gaining momentum. This review discusses scaffolds that have been identified over the last decade from screens of small molecule libraries against Mtb or defined targets where mechanism of action investigation has defined target-hit couples and structure-activity relationship studies have described the pharmacophore.

Thiazole in the targeted anticancer drug discovery

2019 ◽  
Vol 11 (15) ◽  
pp. 1929-1952 ◽  
Author(s):  
Adileh Ayati ◽  
Saeed Emami ◽  
Setareh Moghimi ◽  
Alireza Foroumadi
Keyword(s):  
Drug Discovery ◽  
Cancer Therapy ◽  
Mechanism Of Action ◽  
Anticancer Agents ◽  
Causes Of Death ◽  
Structure Activity ◽  
The World ◽  
Cancerous Cells ◽  
Potential Use ◽  
Anticancer Drug Discovery

Cancer is known as one of the main causes of death in the world; and many compounds have been synthesized to date with potential use in cancer therapy. Thiazole is a versatile heterocycle, found in the structure of many drugs in use as well as anticancer agents. This review provides an overview of recent advances in thiazole-bearing compounds as anticancer agents with particular emphasis on their mechanism of action in cancerous cells. Chemical designs, structure–activity relationships and relevant preclinical properties have been comprehensively described.

Binary encoded small-molecule libraries in drug discovery and optimization

1995 ◽  
Vol 2 (2) ◽  
pp. 305-318 ◽  
Author(s):  
John C. Chabala ◽  
John J. Baldwin ◽  
Jonathan J. Burbaum ◽  
Daniel Chelsky ◽  
Lawrence W. Dillard ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Small Molecule Libraries

scholarly journals Splicing modulators: on the way from nature to clinic

2021 ◽  
Author(s):  
Tilman Schneider-Poetsch ◽  
Jagat Krishna Chhipi-Shrestha ◽  
Minoru Yoshida
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Chemical Biology ◽  
Mrna Processing ◽  
Mrna Splicing ◽  
Scientific Methodology ◽  
Experimental Drugs ◽  
Structure Activity ◽  
Scientific Tool ◽  
Biology Research

AbstractOver the course of more than two decades, natural products isolated from various microorganisms and plants have built the foundation for chemical biology research into the mechanism of pre-mRNA splicing. Hand in hand with advances in scientific methodology small molecule splicing modulators have become powerful tools for investigating, not just the splicing mechanism, but also the cellular effect of altered mRNA processing. Based on thorough structure-activity studies, synthetic analogues have moved on from scientific tool compounds to experimental drugs. With current advances in drug discovery methodology and new means of attacking targets previously thought undruggable, we can expect further advances in both research and therapeutics based on small molecule splicing modulators.

Pyrrolo[2,1-a]isoquinoline scaffold in drug discovery: advances in synthesis and medicinal chemistry

2019 ◽  
Vol 11 (20) ◽  
pp. 2735-2755 ◽  
Author(s):  
Maria D Matveeva ◽  
Rosa Purgatorio ◽  
Leonid G Voskressensky ◽  
Cosimo D Altomare
Keyword(s):  
Multidrug Resistance ◽  
Drug Discovery ◽  
Tumor Cells ◽  
Mechanism Of Action ◽  
Biological Activities ◽  
Antitumor Drugs ◽  
Antitumor Activities ◽  
Structure Activity ◽  
Synthetic Approaches ◽  
Potential Exploitation

Pyrrolo[2,1- a]isoquinoline (PIq) is a nitrogen heterocyclic scaffold of diverse alkaloids endowed with several biological activities, including antiretroviral and antitumor activities. Several 5,6-dihydro-PIq (DHPIq) alkaloids, belonging to the lamellarins’ family, have proved to be cytotoxic to tumor cells, as well as reversers of multidrug resistance. In this review, we provide an overview of the main achievements over the last decade in the synthetic approaches to access libraries of PIq compounds along with a survey, as comprehensive as possible, of bioactivity, mechanism of action, pharmacophore and structure–activity relationships of synthetic analogs of DHPIq-based alkaloids. The focus is mainly on the potential exploitation of the (DH)PIq scaffold in design and development of novel antitumor drugs.

scholarly journals Shortening the drug discovery pipeline: small molecule high content screening for lead discovery in neglected disease

2011 ◽  
Vol 5 (S1) ◽  
Author(s):  
Jonathan Cechetto ◽  
Hee Kyoung Jeon ◽  
Jiyeon Jang ◽  
Doyoon Kwon ◽  
Thierry Christophe ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
High Content Screening ◽  
Lead Discovery ◽  
Neglected Disease ◽  
Discovery Pipeline

scholarly journals Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Saqib Kidwai ◽  
Chan-Yong Park ◽  
Shradha Mawatwal ◽  
Prabhakar Tiwari ◽  
Myung Geun Jung ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mechanism Of Action ◽  
Chemotherapeutic Agents ◽  
Intracellular Bacteria ◽  
Dependent Manner ◽  
Content Type ◽  
Structure Activity ◽  
Dual Mechanism

ABSTRACT New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to fbiB and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F420-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10-phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for in vitro activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved in vitro activity and in vivo efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against Mycobacterium tuberculosis, 5NP also modulates the host machinery to kill intracellular pathogens.

Sign in / Sign up

Export Citation Format

Share Document