Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

Abstract

Development of new chemotherapeutic drugs is the need of the hour to improve tuberculosis control, particularly in the developing world. In the last fourty years no new compound has been brought to the market for the treatment of tuberculosis. However, in recent years there is an enhanced activity in the research and development of new drugs for TB. Some compounds are presently in clinical development, while others are being investigated pre-clinically in an attempt to explore new molecules for the target based treatment of TB. Simultaneously some new targets are being identified and validated for their practical usefulness. Structures based on thiolactomycin could have considerable potential in the development of target based anti-TB agents. The present review provides an overview of the drugs that are being clinically used and the compounds that are in advanced stages of clinical as well as preclinical studies. We have also attempted to highlight the efforts that are being made in the development of new molecules based on thiolactomycin as lead compound, including studies from this laboratory.

Development of nitroimidazopyrans and nitroimidaoxazoles for tuberculosis chemotherapy

“…Recent insights into mechanisms that neutralize the toxicity of antibiotics in the cytoplasm have revealed other systems that function in synergy with the permeability barrier and efflux systems to provide natural resistance. Drugs inhibiting these intrinsic systems would enable many antibiotics, which are already available but have not been used for TB, to gain new activities against Mtb [17].…”

“…The main difference is that XDR-TB is associated with a much higher mortality rate than MDR-TB, because of the reduced number of effective treatment options. Hence, there is an urgent need for novel drugs that are active against Mtb in order to shorten the duration of tuberculosis therapy [17].…”

“…Mtb possesses a cell wall dominated by covalently linked mycolic acids, arabinogalactan and peptidoglycan (AGP), the mycolic acids of which are complemented by glycolipids such as α,α-trehalose monomycolate (TMM). This mycolic acid based permeability barrier shields the organism from environmental stress and contributes to resistance against many antibiotics [17].…”

“…Typically, the phagosome fuses with the lysosome which contains degradative enzymes, low pH, reactive oxygen species, etc., to destroy foreign particles. As the bacterium multiplies, it kills the macrophage, releasing more bacteria to be taken up by more macrophages [17].…”

Recent Efforts for the Development of Antitubercular Drug Containing Diazine Ring

“…Compounds 2a-h and 3a-h 1a-1d R 1 =H, 1e-1h R 1 =F, 1i-1l R 1 =Cl 2a-2h R=p-Cl, 3a-3h R=p-CH 3 ; 2a and 3a R'=H; 1a, 1e and 1i R 2 =H; 1b, 1f, and 1j R 2 =Br 2b and 3b R'=p-Cl; 2c and 3c R'=p-NO 2 ; 2d and 3d R'=p-OH; 1c, 1g and 1k R 2 =Cl; 1d, 1h and 1l R 2 =F 2e and 3e R'=p-CH 3 ; 2f and 3f R'=p-OCH 3 , 2g and 3g R'=p-OH, m-OCH 3 ; 2h and 3h R'=p-F Two series of pyridazinone derivatives (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) were evaluated for anti-TB activities against Mtb H37Rv strain. The compound 2g, 5-(4-hydroxy-3-methoxybenzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone emerged as a lead compound with good anti-TB activity.…”