Tuberculosis: The drug development pipeline at a glance

Abstract

Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60's of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis.

Search for synthetic and natural substances with in vitro bioactivity against Mycobacterium tuberculosis. Part I

“…Sin embargo, dado que en M. tuberculosis no se ha demostrado la existencia de ésta última enzima, la actividad biológica podría estar concentrada en la girasa de ADN como única diana, implicando esto un tipo de acción sub óptima del fármaco. Ahora bien, GATI y MOXI han presentado mejor actividad in vitro contra M. tuberculosis H37Rv que otras fluoroquinolonas, con CMI de 0.12-0.25 µg/mL y 0.18-0.5 µg/mL respectivamente (Villemagne et al, 2012;Gatifloxacin, 2008;Moxifloxacin, 2008). En la actualidad los dos fármacos han superado los ensayos clínicos de fase I y II.…”

“…En la actualidad los dos fármacos han superado los ensayos clínicos de fase I y II. La fase III está en proceso y su principal objetivo es evaluar la eficacia y seguridad de los fármacos y la posibilidad de reducir el tiempo de tratamiento de 6 a 4 meses (Villemagne et al, 2012;Coll, 2009). …”

Hybrid imidazole (benzimidazole)/pyridine (quinoline) derivatives and evaluation of their anticancer and antimycobacterial activity

“…138.51 C-4, 138.67 C-11, 148.22 C-2, 151.31 C-6, 164.60 C-8, 0 -H), 7.99 (brs, 1H, 5-H), 8.37 (ad, J ¼ 3.5 Hz, 1H, 2-H), 9.11 (as, 1H, 11-H), 11.07 (s, 1H, 7-H). 13 3 3 C-4a, 131.16 C-18a, 131.35 C-14a, 134.00 C-8, 136.71 C-4, 138.36 C-8a, 144.63 C-13, 149.14 C-2, 164.13 C-2 0 , 166.55 C-10. …”

“…The IR spectra were recorded on an FTIR Shimadzu Prestige 8400s spectrophotometer (Kyoto, Japan). Proton and carbon nuclear magnetic resonance ( H , C ) spectra were recorded on a Bruker Avance III 500 spectrometer operating at 500 MHz for 1 H and 125 MHz for 13 C. The following abbreviations were used to designate chemical shift multiplicities: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, brs ¼ broad singlet, as ¼ apparent singlet, ad ¼ apparent doublet, at ¼ apparent triplet, aq ¼ apparent quartet, dd ¼ doublet of doublets, td ¼ triplet of doublets, and m ¼ multiplet. All chemical shifts are quoted on the -scale in ppm.…”

Potent Oxazolidinone Antibacterials with Heteroaromatic C-Ring Substructure

“…15 Although this scaffold has not been investigated for activity against Gram-positive or -negative bacteria, the oxazolidinone antibacterial sutezolid (5) is known to exhibit strong in vitro activities against both Gram-positive bacteria (such as MRSA) and Mycobacterium tuberculosis. 16 Since the above heteroaromatic ring system showed antimycobacterial activity, we suspected that it might also have antibacterial activity potential because antimycobacterial activity is generally correlated with antibacterial activity toward Gram-positive bacteria such as MRSA. Therefore, we expected that introduction of the above pyrazolo[1,5-a]pyridine or a related scaffold into oxazolidinone antibacterials might result in potent antibacterial activity.…”