Tuberculosis (TB) is one of the most devastating diseases primarily due to several decades of neglect, and presents a global health threat of escalating proportions. TB is the second leading ...infectious cause of mortality today behind only HIV/AIDS. The impetus for developing new structural classes of anti-tuberculosis drugs comes from the emergence of multi-drug resistant (MDR) strains to commonly used drugs, substantially longer durations of therapy that are needed as a result of resistance, and the resurgence of disease in immunocompromised patients. Recent years have witnessed emergence of many new structural classes of anti-TB agents, which have exhibited promising activities against drug-sensitive and drug-resistant strains of the causative organism Mycobacterium tuberculosis. These analogs ideally should decrease the overall duration of therapy with improved efficacy, and exhibit mechanisms of action different from those of existing drugs to counter the resistant strains of M. tuberculosis. This review provides a comprehensive literature compilation on advances in the new structural classes of anti-TB analogs reported during the past five years. Our discussion and observations are concentrated on chemotherapeutic potential of alphabetically listed twenty-seven new structural classes of anti-tuberculosis agents that include:- acetamides, 5-arylidene-2-thiohydantoins, benzoxazoles and benzothiazoles, benzoic acid hydrazones, benzoxazines, carbohydrates, chalcones, coumarins, deazapteridines, imidazoles, indoloquinazolinones, isothiosemicarbazones, mycobactins, 1,8- naphthyridines, phenazines, purines, pyridines, N-pyridinylsalicylamides, pyrimidines and thymidines, pyrroles, quinolines, quinoxalines, terpenes, thiadiazine thiones, thiolactomycines, toludines, and triazoles.
Structural optimization of the previously identified 4-(adamantan-1-yl)-2-quinolinecarbohydrazide (AQCH, MIC
=
6.25
μg/mL, 99% inhibition,
Mycobacterium tuberculosis H37Rv) has led to two series of ...4-(adamantan-1-yl)-2-substituted quinolines (Series 1–2). All new derivatives were evaluated in vitro for antimycobacterial activities against drug-sensitive
M. tuberculosis H37Rv strain. Several 4-adamantan-1-yl-quinoline-2-carboxylic acid
N′-alkylhydrazides (Series 1) described herein showed promising inhibitory activity. In particular, analogs
7,
9,
20, and
21 displayed MIC of 3.125
μg/mL. Further investigation of AQCH by its reaction with various aliphatic, aromatic, and heteroaromatic aldehydes led to the synthesis of 4-adamantan-1-yl-quinoline-2-carboxylic acid alkylidene hydrazides (Series 2). Analogs
42–
44 and
48 have produced promising antimycobacterial activities (99% inhibition) at 3.125
μg/mL against drug-sensitive
M. tuberculosis H37Rv strain. The most potent analog
35 of the series produced 99% inhibition at 1.00
μg/mL against drug-sensitive strain, and MIC of 3.125
μg/mL against isoniazid-resistant TB strain. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by three methods—comparative molecular field analysis (CoMFA), CoMFA with inclusion of a hydropathy field (HINT), and comparative molecular similarity indices analysis (CoMSIA). Several statistically significant CoMFA, CoMFA with HINT, and CoMSIA models were generated. Prediction of the activity of a test set of molecules was the best for the CoMFA model generated with database alignment. Based on the CoMFA contours, we have tried to explain the structure–activity relationships of the compounds reported herein.
The bicyclic 4‐nitroimidazoles PA‐824 and OPC‐67683 represent a promising novel class of therapeutics for tuberculosis and are currently in phase II clinical development. Both compounds are pro‐drugs ...that are reductively activated by a deazaflavin (F420) dependent nitroreductase (Ddn). Herein we describe the biochemical properties of Ddn including the optimal enzymatic turnover conditions and substrate specificity. The preference of the enzyme for the (S) isomer of PA‐824 over the (R) isomer is directed by the presence of a long hydrophobic tail. Nitroimidazo‐oxazoles bearing only short alkyl substituents at the C‐7 position of the oxazole were reduced by Ddn without any stereochemical preference. However, with bulkier substitutions on the tail of the oxazole, Ddn displayed stereospecificity. Ddn mediated metabolism of PA‐824 results in the release of reactive nitrogen species. We have employed a direct chemiluminescence based nitric oxide (NO) detection assay to measure the kinetics of NO production by Ddn. Binding affinity of PA‐824 to Ddn was monitored through intrinsic fluorescence quenching of the protein facilitating a turnover‐independent assessment of affinity. Our results indicate that (R)‐PA‐824, despite not being turned over by Ddn, binds to the enzyme with the same affinity as the active (S) isomer. This result, in combination with docking studies in the active site, suggests that the (R) isomer probably has a different binding mode than the (S) with the C‐3 of the imidazole ring orienting in a non‐productive position with respect to the incoming hydride from F420. The results presented provide insight into the biochemical mechanism of reduction and elucidate structural features important for understanding substrate binding.
PA‐824, a bicyclic‐nitroimidazole in clinical development against tuberculosis, is bioreductively activated by a deazaflavin (F420) dependent nitroreductase (Ddn). Substrate and stereospecificity of Ddn is directed by the presence of a long hydrophobic tail. (R)‐PA‐824 binds Ddn with the same affinity as the active (S)‐PA‐824, despite not being turned over. Docking studies suggest that (R)‐PA‐824 likely binds non‐productively to the enzyme.
During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology ...thereby inaccurately predicting clinical outcome. We found that Nos2
mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2
mice with TB to monotherapy before or after establishment of human-like pathology. Isoniazid induced a drug-tolerant persister population only when necrotic lesions were present. Rifapentine was more potent than rifampin prior to development of human-like pathology and equally potent thereafter, in agreement with recent clinical trials. Pretomanid, delamanid and the pre-clinical candidate BTZ043 were bactericidal independent of pulmonary pathology. Linezolid was bacteriostatic in TB-infected Nos2
mice but significantly improved lung pathology. Hypoxic necrotizing lesions rendered moxifloxacin less active. In conclusion, Nos2
mice are a predictive TB drug development tool owing to their consistent development of human-like pathology.
We have previously identified ring-substituted quinolines as a new structural class of anti-tuberculosis agents. In our ongoing efforts at structural optimization of this class, four series of ...ring-substituted-2/4-quinolinecarbaldehyde derivatives were synthesized. All twenty-four compounds were synthesized using short and convenient one to two high yielding steps. The newly synthesized compounds were tested in vitro against drug-sensitive
Mycobacterium tuberculosis H37Hv strain. Several derivatives were found to be promising inhibitors of
M. tuberculosis. For example, derivatives
4a–
c (Series 2),
7a–
d (Series 3), and
8a–
b (Series 4) displayed >90% inhibition at 6.25
μg/mL in the primary assay. The most active compounds,
N-(2-fluorophenyl)-
N′-quinolin-2-ylmethylene-hydrazine (
4a),
N-(2-adamantan-1-yl-quinolin-4-ylmethylene)-
N′-(4-fluorophenyl)hydrazine (
7c), and
N-(2-cyclohexyl-quinolin-4-ylmethylene)-
N′-(2-fluorophenyl)hydrazine (
8a), exhibited 99% inhibition at the lowest tested concentration of 3.125
μg/mL against drug-sensitive
M. tuberculosis H37Rv strain. The similarity index based on steric and electrostatic features of the molecules was used, in conjunction with principal component analysis and linear discriminant analysis, successively to classify the molecules based on their activity into two classes. This classification method gives us confidence in predicting the activity class of any new unsynthesized molecule belonging to these series.
A 3D-QSAR analysis of a new class of ring-substituted quinolines with anti-tuberculosis activity has been carried out by three methods—Comparative Molecular Field Analysis (CoMFA), CoMFA with ...inclusion of a hydropathy field (HINT), and Comparative Molecular Similarity Indices Analysis (CoMSIA). The conformation of the molecules was generated using a simulated annealing protocol and they were superimposed using features common to the set with
database alignment (SYBYL) and field fit methods. Several statistically significant CoMFA, CoMFA with HINT, and CoMSIA models were generated. Prediction of the activity of a set of test molecules was the best for the CoMFA model generated with
database alignment. Based upon the information contained in the CoMFA model, we have identified some novel features that can be incorporated into the quinoline framework to improve the activity.
PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the ...driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC). In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in vivo PK and efficacy studies. In an established murine TB model, the efficacy of diverse nitroimidazole analogs ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Further, a retrospective analysis was performed for a set of seven nitroimidazole analogs to identify the PK parameters that correlate with in vivo efficacy. Our findings show that the in vivo efficacy of bicyclic 4-nitroimidazoles correlated better with lung PK than with plasma PK. Further, nitroimidazole analogs with moderate-to-high volume of distribution and Lung to plasma ratios of >2 showed good efficacy. Among all the PK-PD indices, total lung T>MIC correlated the best with in vivo efficacy (rs = 0.88) followed by lung Cmax/MIC and AUC/MIC. Thus, lung drug distribution studies could potentially be exploited to guide the selection of compounds for efficacy studies, thereby accelerating the drug discovery efforts in finding new nitroimidazole analogs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intra-oral schwannoma- a case report Parhar, Swati; Singh, Harkanwal Preet; Nayyar, Amit ...
Journal of clinical and diagnostic research,
03/2014, Letnik:
8, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Neurilemmoma (Schwannoma) is a benign tumour of neuroectodermal origin. It usually occurs as a asymptomatic, solitary, smooth-surfaced and slow growing lesion, emerging at any age, with as such, no ...gender prelidiction. Occurring as a common tumour in the head and neck region, its intraoral presentation is very rare. Here, we are reporting a rare case of intraoral schwannoma of the posterior palate which occurred in a 34-year-old female patient who had chief complaint of a painless, slow growing swelling on posterior palate.
We report synthesis and anti-tuberculosis activities of a series of novel ring-substituted quinolines. The most effective compound of the series
3d (MIC=6.25 μg/mL,
Mycobacterium tuberculosis H37Rv ...strain) was synthesized in one step; thus is an attractive lead molecule for anti-tuberculosis drug development. The results of this study represent the discovery of ring-substituted 4-methylquinolines as new class of potential anti-tuberculosis agents.
The synthesis and antimycobacterial activities (
Mycobacterium tuberculosis H37Rv strain) for a series of ring-substituted 4-methylquinolines are described. The evaluation of cytotoxicity and efficacy against
M. avium and single-drug-resistant (SDR) strains of
M. tuberculosis for the most effective compound
3d (
R=
c-C
5H
9) are also reported.
PDF
