10 Major Novel Chemical Entities | Tuberculosis

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.