This article throws light upon the ten novel chemical entities in herbal drugs. Some of the novel entities are: 1. Diarylquinoline TMC207 2. Nitro imidazole PA-824 4. Pyrrole LL-3858 5. Pleuromutilins 6. Di-piperidine SQ-609 7. ATP Synthase Inhibitor FAS20013 8. Translocase I inhibitor
Novel Chemical Entity # 1. Diarylquinoline TMC207:
Thediarylquinoline TMC207 (Fig. 6.1a, Table 6.1), an extremely promising member of a new class of anti-mycobacterial agents, has a potent early and late bactericidal activity in the non-established infection in murine TB model exceeding that of INH.
The substitution of RIF, INH or PZA with diarylquinoline TMC207 accelerated activity leading to complete culture conversion after 2 months of treatment in some combinations.
The diarylquinoline-isoniazid-pyrazinamide with diarylquinoline-rifampicin-pyrazinamide combinations cleared the lungs of TB in all mice after 2 months. Diarylquinoline TMC207 also has been tested in various combinations with the second line drugs such as amikacin, PZA, moxifloxacin and ethionamide in mice infected with the drug- susceptible virulent M. tuberculosis H37RV strain.
The target and mechanism of action of diarylquinoline TMC207 is different from those of other anti-TB agents implying low probability of cross-resistance with existing TB drugs.
It is further suggested that diarylquinoline TMC207 is able to inhibit bacterial growth, when tested on MDR-TB isolates, by inhibiting ATP synthase leading to ATP depletion and pH imbalance. About 20 molecules of this agent have been shown to have an MIC of below 0.5 µg/mL against M. tuberculosis H37RV strain.
Antimicrobial activity was confirmed in vivo for three of these molecules. A thorough assessment of diarylquinoline activity against MDR-TB in vivo would however require testing of animal models infected with multi-drug resistant bacterial strains rather than with drug-susceptible strains. Diarylquinoline TMC207 is currently in Phase II Clinical Trials.
Novel Chemical Entity # 2. Nitro imidazole PA-824:
Nitro imidazole PA-824 (Fig. 6.1), is a new nitro imidazole derivative developed by PathoGenesis-Chiron in 1995 and currently being developed by the TB Alliance.
The TB Alliance received worldwide exclusive rights to PA- 824 and its analogs for the treatment of TB. PA-824 entered Phase I clinical trials in June 2005. In vitro, PA-824 showed high activity against drug-sensitive and drug-resistant M. tuberculosis strains, indicating that there is no cross-resistance with current TB drugs.
Experiments performed on mice showed that the administration of PA-824 at doses ranging from 25.0 -100.0 mg/mL produced reductions in the bacterial burden in the spleen and lungs when compared to that produced by INH at 25 mg/mL.
Further-investigations are required to assess the potentiality of PA-824 to improve the treatment of both drug- susceptible and multi-drug resistant tuberculosis when used in novel combinations with new drug candidates in addition to existing anti-tuberculosis drugs. Nitro imidazole PA-824 is currently in Phase II Clinical Trials (Table 6.1).
Novel Chemical Entity # 3. Nitro Imidazole OPC-67683:
Nitro imidazole OPC-67683 (Fig. 6.1c) belongs to a subclass of mycolic acid inhibitors, which interferes with the biosynthesis of the mycobacterial cell wall. MIC’s of this compound were determined using standard and clinical isolated M. tuberculosis strains, including MDR strains.
In vitro, OPC- 67683 showed high activity against drug-sensitive as well as drug-resistant strains with MIC’s ranging from 6.0 – 24.0 mg/mL and also strong intracellular activity against M. tuberculosis H37RV strain residing within human macrophages.
Studies in animal models showed that OPC- 67683 is effective against sensitive H37RV and MDR-TB strains in vivo starting from a concentration of 0.03125 mg/body. The TB Alliance is currently negotiating with Otsuka Pharmaceuticals concerning the further joint development of this compound. OPC-67683 is in Phase II Clinical Trials.
Novel Chemical Entity # 4. Pyrrole LL-3858:
Very little information on the development of pyrroles as anti-mycobacterial agents is currently available. Pyrroles derivatives were found to be active against standard and drug- sensitive M. tuberculosis strains in vitro.
Lupim Limited reported the identification of a pyrrole derivative (LL-3858) that showed higher bactericidal activity than INH when administered as mono-therapy to infected mice. In mice models, a 12 weeks treatment with LL-3858 plus INH and RIF, or LL-3858 plus INH-RIF-PZA, sterilized the lungs of all infected mice.
Experiments conducted in mice and dogs showed that the compound is well absorbed, with levels in serum above the MIC. No information is available concerning the molecular mechanisms that mediate LL-3858’s bacterial activity. Pyrrole LL- 3858 is in Phase II Clinical Trial (Table 6.1).
Novel Chemical Entity # 5. Pleuromutilins:
The pleuromutilins represent a novel class of antibiotics derived from a natural product. They interfere with protein synthesis by binding to the 23S rRNA and therefore inhibiting the peptide bond formation.
Recent studies showed that cross-resistance might occur among pleuromutilins and oxazolidinones. Pleuromutilins have also showed to inhibit the growth of M. tuberculosis in vitro.
Novel Chemical Entity # 6. Di-Piperidine SQ-609:
Di-piperidine SQ-609 is a novel compound structurally unrelated to existing anti-TB drugs. It kills M. tuberculosis by interfering with cell wall biosynthesize. Antimicrobial activity has been demonstrated in vivo in mice models.
Novel Chemical Entity # 7. ATP Synthase Inhibitor FAS20013:
FAS20013 is a novel compound identified by Fasgen. It belongs to the class of a- sulphonylcarboxamides. Fasgen claims that FAS20013 will kill more organisms in a 4 hour exposure that INH or RIF can during a 12-14 day exposure. The compound is very effective in killing MDR-TB organisms that are resistant to the multiple drugs currently in use.
A series of recent laboratory experiments indicate the superior effect of FAS20013 as compared to current drugs in terms of its ability to sterilize TB lesions and kill latent TB. Therapeutic evaluation of FAS20013 has repeatedly shown its effectiveness in mice, but it appears to or has no serious side effects.
The compound is up to 100% bio-available when administered orally. To date no dose-limiting toxicity has been encountered, even when doses are 10 times administered. The compound is thought to act through inhibition of ATP synthase, however the available publications assessing the efficacy of this compound are of poor quality.
Novel Chemical Entity # 8. Translocase I inhibitor:
These are compounds which specifically inhibit mycobacterial translocase I, an enzyme required for bacterial cell wall. Preclinical evaluations of the compounds are planned.
Novel Chemical Entity # 9. InhA Inhibitors:
Frontline drugs such as INH target the enoyl reductase enzyme InhA, found in M. tuberculosis which catalyses the last step in the fatty acid synthase pathway. Drug resistance to INH results primarily from KatG (the enzyme that activates INH), therefore the InhA inhibitors that do not require activation by KatG are attractive candidates in the search for new drugs.
The main purpose is to bypass the activation step and directly inhibit InhA. A possible limitation for this kind of compound is that cross-resistance with INH may easily occur.
Novel Chemical Entity # 10. Isocitrate Lyse Inhibitors:
The isocitrate lyase (ICL) enzyme has been shown to be essential for long-term persistence of M. tuberculosis in mice, but not required for bacilli viability in normal culture.
McKinney and collaborators have shown that inhibition of ICL1 and ICL2 (the two isoforms of isocytrate lyase present in M. tuberculosis), blocks the growth and survival of M. tuberculosis in macrophages and in mice at an early and late stage of infection.
GSK planned in 2000 to screen 400 000 ICL inhibitors as potential therapeutic drugs. Up to now 900 000 compounds have been screened but no successful inhibitors have been identified. The structure of the ICL active site makes the screening of inhibitors lengthy and the active site of this enzyme appears not to be easily reached by compounds.