New antimycobacterial agents in the pre-clinical phase or beyond: recent advances in patent literature (2001–2016)

Abstract

Tuberculosis, an infectious disease, has caused more deaths worldwide than any other single infectious disease, killing more than 1.5 million people each year; equating to 4,100 deaths a day. In the past 60 years, no new drugs have been added to the first line regimen, in spite of the fact that thousands of papers have been published on drugs against tuberculosis and hundreds of drugs have received patents as new potential products. Thus, there is undoubtedly an urgent need for the deployment of new effective drugs against tuberculosis. Areas covered: This review brings to the reader the opportunity to understand the chemical and biological characteristics of all patented anti-tuberculosis drugs in North America, Europe, Japan, and Russia. The 116 patents discussed here concern new molecules in the early or advanced phase of development in the last 16 years. Expert opinion: Of all 116 patents, only one developed drug, bedaquiline, is used, and then, only in specific cases. Another three drugs are in clinical studies. However, many other compounds, for which there are in vitro and in vivo studies, seem to fulfil the requisite criteria to be a new anti-tuberculosis agent. However, why are they not in use? Why were so many studies interrupted? Why is there no more news for many of these drugs?

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

“…MmpL3 transports trehalose monomycolates (TMMs) across cell envelop for subsequent incorporation into trehalose dimycolates or arabinogalactan during Mtb cell wall biosynthesis [ 158 ]. Although structurally similar to ethambutol, SQ-109 exhibits a different mechanism of action and has activity against ethambutol-resistant Mtb isolates [ 57 , 115 ]. The compound has gone through a phase II clinical trial [ 159 ].…”

“…BTZ-043 is a piperidine-containing benzothiazinone prodrug activated through bioreduction of its nitro group by mycobacterial enzymes (including DprE1) to yield a nitroso metabolite [ 115 , 165 ]. This metabolite reacts with the thiol group of a cysteine residue (Cys387) in the substrate-binding site of DprE1 to form a covalent bond that irreversibly inhibits DprE1, thus classifying BTZ-043 as a suicide inhibitor [ 178 ].…”

Dibasic Derivatives of Phenylcarbamic Acid Against Mycobacterial Strains: Old Drugs and New Tricks?

“…The treatment of commonly encountered species of tuberculous and non-tuberculous mycobacteria responsible for a multiplicity of different types of infections, including pulmonary, respiratory, cutaneous, and systemic infections, by (i) brand new classes of promising compounds preferably acting on novel targets; or (ii) ‘non-typical’ antimycobacterial drug candidates is still in very dynamic and progressive debate [ 1 , 2 , 3 , 4 , 5 , 6 ]. The strategy was successfully used in a case of in vitro screening of some β-lactam antibiotics (ceftaroline or ceftazidime) in a combination with an β-lactamase inhibitor avibactam against Mycobacterium avium complex [ 3 , 4 ].…”

Bedaquiline: Fallible Hope Against Drug Resistant Tuberculosis

“…One such lead was achieved with the production of rifamycin B natural analog, 24-desmethylrifamycin B by manipulating the rifamycin polyketide synthase gene cluster in the producer organism Amycolatopsis mediterranei S699 [5,[12][13][14]. Notably, no new drug could be added to the first line regimen in the last 60 years even after thousands of publications and hundreds of patents related to the anti-TB drugs [15]. From these entire patented molecules only one novel drug, BDQ, could be included into anti-TB regimen [15].…”

“…Notably, no new drug could be added to the first line regimen in the last 60 years even after thousands of publications and hundreds of patents related to the anti-TB drugs [15]. From these entire patented molecules only one novel drug, BDQ, could be included into anti-TB regimen [15].…”