Triazole And Anti - Tuberculosis Activity Studies And 3 - Hydroxymorphinan And Anti - Parkinson 's Disease

Tuberculosis (TB), which is caused mainly by Mycobacterium tuberculosis (MTB), is the second most prevalent infectious disease worldwide. With the growing number of multi-drug resistant strains of M.tuberculosis (MDRTB), there is an urgent need to discover new targets for antituberculotics and develop novel antituberculotics. Shikimate dehydrogenase, an essential protein for the biosynthesis of the chorismate end product, is critical for the virulence and viability of several pathogenic microbes, including Mycobacterium tuberculosis, yet the shikimate pathway is absent from mammalian. Shikimate dehydrogenase have therefore been a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents.The National Center for Drug (microorganism) Screening have established a high-throughput screening (HTS) model targeting Mycobacterium tuberculosis shikimate dehydrogenase (MtSD) for the discovery of novel antituberculosis drugs.80,000 compounds were screened using this model and evaluated for their activity against Mtb H37Rv. One 3,6-disubstituted triazolothiadiazole (IMB-CC223, MIC-H37Rv = 8.0 μg/mL; MIC-MDRTB = 8.0 μg/mL; MIC-RDRTB = 8.0 μg/mL; Mt SD-IC50 = 23.00 μg/mL; RDRTB, Rifampin-resistant TB) has been identified as a promising lead for antitubercular drug development. On the principles of group replacement, scaffold hopping, bioisosterism, we designed and synthesized 125 compounds, including 101 derivatives of the hit compound IMB-CC223, and got some preliminary structure-activity relationships after determining their anti-TB activities and MtSD inhibitory effect in vitro. Some compounds exhibited good to excellent activity.17 triazolothiadiazoles are approximately 2-32 fold more active than IMB-CC223 against H37Rv,2-8 fold more potent than Rifampin (RMP) against MDRTB, and 2-32 fold in activity to RMP against RDRTB, wherein 6b-5,6d-3 and 6d-4 are 2-fold more active than Isoniazid (INH) against RDRTB, and one compound is comparable in activity to IMB-CC223. It has been found that the nature of the substitute group on the para site of 3-phenyl exerts remarkable effects on the antitubercular activity. For example, electron-donating (4-methoxy) and unsubstituted groups are detrimental to the activity. On the contrary, halogen groups, i.e., fluoro, chloro and bromo groups, at this position dramatically increase the potency. Subsequently, benzene ring at the 3 position is replaced with a pyridine ring. Unfortunately, these modifications result in a dramatic attenuation of activity, compared to the MIC value of IMB-CC223. The nature of phenoxymethyl group at the 6 position exhibits substantial effects on the potency. Bromo, chloro, fluoro, nitro and methoxy groups in the para position of the benzene ring at the 6 position are well tolerated.6 triazolothiadiazines are approximately 2-32 fold more active than IMB-CC223 against H37Rv,4-8 fold more potent than Rifampin (RFP) against MDRTB, and 4-64 fold in activity to RFP against RDRTB, wherein 7d-3 are 4-fold more active than Isoniazid (INH) against RDRTB, and 4 compounds are comparable in activity to IMB-CC223. It has been found that electron-donating (4-methoxy) on the para site of 3-phenyl is detrimental to the activity. On the contrary, bromo group, at this position dramatically increases the potency. Moreover, fluoro group on the para site of 6-phenyl results in a dramatic attenuation of activity, compared to the MIC value of IMB-CC223. To confirm that two series of compounds actually target MtSD, the 17 potent compounds were selected for further evaluation of their in vitro MtSD inhibitory activity. Fortunately, the potent derivatives,6c-4,6c-8,6d-4 and 7f-3 display potential inhibitory activity on MtSD (6c-4, MtSD-IC50= 6.82 μg/mL; 6c-8, MtSD-IC50 = 9.37 μg/mL; 6d-4, MtSD-IC50 = 14.42 μg/mL; 7f-3, MtSD-IC50 = 11.68 μg/mL), which demonstrates the extent of inhibitory effect on MtSD correlates to the extent of antitubercular activity. Further, some of the potent derivatives synthesized were tested to assess their apparent cytotoxicity toward Vero and HepG2 cells. Consequently, we are pleased to notice that most compounds are apparently not toxic (SI>10), while maintaining good activity compared with the hit compound IMB-CC223. Unfortunately, modifications of 6c-8,6d-9 and 7f-3 leading to an enhancement of activity, also result in a counterproductive improvement of cytotoxicity. Since these new highly potent MtSD inhibitors act on a new target and possess unique chemical structures with existing antituberculotics, they are worthy to be further studied and developed.Currently, the therapeutic methods of Parkinson disease (PD) are only limited to symptomatic and supportive treatment, but radically failed to stop the progression of the underlying disease. Although levodopa and other drugs to treat Parkinson’s can relieve or control the symptoms of the disease, but is no effect for the death of progressive nerve cells. In other words, when a large number of neuronal loss, these drugs will no longer play any role. Thus, the research of neuroprotective drug that can delay, prevent or even reverse the neuronal degeneration will be the inevitable trend of the future treatment of neurodegenerative diseases.3-hydroxymorphinan (3-HM) has a very good neuroprotective effect, and does not produce neurotoxicity. But now 3-HM has a shortcoming of low oral bioavailability because of extensive O-glucuronidation of the phenol, only 18%. So it is only effective when administered intraperitoneally or intravenously. We envisioned that a suitably arranged heterocycle with an NH group would serve as metabolically stable isostere of the phenolic group so as to improve the metabolic stability and overall PK profile of 3-HM. Subsequently, based on an iterative design process, we designed and synthesized 2 analogues of 3-HM. Wherein benzimidazolone imidazolone-morphinan is comparable in activity to 3-HM against lipopolysaccharide (LPS)-induced inflammatory responses in microglial BV2 cells. Moreover, imidazolone-morphinan did not exhibit cytotoxicity against microglia. Relevant in vivo animal experiments (LPS-induced PD model rats) is being carried out. Currently, no clinical drug is applicatory in this field, therefore, this research is of great clinical significance and application prospects.