Synthesis and antitubercular evaluation of 2-iminothiazolidine-4-ones

In the present manuscript, we report synthesis of new 3 and 5 substituted 2-imino thiazolidine-4-ones by three step synthetic protocols from 3-trifluormethyl aniline or 2-amino heterocycle. The compounds were evaluated for in vitro activities against Mycobacterium tuberculosis (MTB) in presence and absence of efflux pump inhibitor, cytotoxicity against RAW 264.7 cells. Among the thirty six compounds, 2-imino-3-(5-nitrothiazol-2-yl)-5-(3,4,5-trimethoxybenzylidene)thiazolidin-4-one (5g) was found to be the most active compound in vitro with MICs of 3.31 µM against log-phase culture of MTB and also non-toxic up to 100 µM. Compound 5g showed minimum inhibitory concentration (MIC) of 0.82 µM against MTB in presence of efflux pump inhibitor verapamil

Salicylanilide Diethyl Phosphates as Potential Inhibitors of Some Mycobacterial Enzymes

Antimycobacterially active salicylanilide diethyl phosphates were evaluated to identify their potential drug target(s) for the inhibition of several mycobacterial enzymes, including isocitrate lyase, L-alanine dehydrogenase (MtAlaDH), lysine ε-aminotransferase, chorismate mutase, and pantothenate synthetase. The enzymes are related to the nongrowing state of Mycobacterium tuberculosis. Salicylanilide diethyl phosphates represent new candidates with significant inhibitory activity especially against L-alanine dehydrogenase. The most active MtAlaDH inhibitor, 5-chloro-2-[(3-chlorophenyl)carbamoyl]phenyl diethyl phosphate, has an IC50 of 4.96 µM and the best docking results. Other mycobacterial enzymes were mostly inhibited by some derivatives but at higher concentrations; isocitrate lyase showed the highest resistance to salicylanilide diethyl phosphates

Depletion of M. tuberculosis GlmU from infected murine lungs effects the clearance of the pathogen

M. tuberculosis N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmUMtb) is a bi-functional enzyme engaged in the synthesis of two metabolic intermediates N-acetylglucosamine-1-phosphate (GlcNAc-1-P) and UDP-GlcNAc, catalyzed by the C- and N-terminal domains respectively. UDP-GlcNAc is a key metabolite essential for the synthesis of peptidoglycan, disaccharide linker, arabinogalactan and mycothiols. While GlmUMtb was predicted to be an essential gene, till date the role of GlmUMtb in modulating the in vitro growth of Mtb or its role in survival of pathogen ex vivo / in vivo have not been deciphered. Here we present the results of a comprehensive study dissecting the role of GlmUMtb in arbitrating the survival of the pathogen both in vitro and in vivo. We find that absence of GlmUMtb leads to extensive perturbation of bacterial morphology and substantial reduction in cell wall thickness under normoxic as well as hypoxic conditions. Complementation studies show that the acetyl- and uridyl- transferase activities of GlmUMtb are independently essential for bacterial survival in vitro and GlmUMtb is also found to be essential for mycobacterial survival in THP-1 cells as well as in guinea pigs. Depletion of GlmUMtb from infected murine lungs, four weeks post infection, led to significant reduction in the bacillary load. The administration of Oxa33, a novel oxazolidine derivative that specifically inhibits GlmUMtb, to infected mice resulted in significant decrease in the bacillary load. Thus our study establishes GlmUMtb as a strong candidate for intervention measures against established tuberculosis infections

Sinteza N4-(2,4-dimetilfenil) semikarbazona kao inhibitori 4-aminobutirat aminotransferaze

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formations. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models including maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (scSTY) seizure threshold tests. The compounds were also evaluated for behavioural impairement and depression activity. In the neurochemical investigation, potent compounds were evaluated for their effects on rat brain -aminobutyric acid levels and in vitro -aminobutyrate transaminase (Pseudomonas fluorescens) activity. Preliminary studies suggest these compounds to exhibit anticonvulsant activity via GABA-mediated mechanism.Sintetizirano je nekoliko 2,4-dimetilfenil supstituiranih semikarbazona u tri sintetska koraka koji uključuju aril uree i aril semikarbazide. Strukture spojeva su potvrđene spektroskopskim metoda i elementarnom analizom. Ispitano je antikonvulzivno djelovanje novih spojeva nakon izazivanja konvulzija elektrošokom te supkutanom primjenom pentilentetrazola ili strihnina. Osim toga, testirano je antidepresivno djelovanje te učinak tih spojeva na ponašanje štakora. Praćen je njihov utjecaj na koncentraciju gama-aminomaslačne kiseline (GABA) u mozgu štakora te in vitro na aktivnost gama-aminobutirat transaminaze (Pseudomonas fluorescens). Preliminarni pokusi ukazuju da antikonvulzivno djelovanje ovih spojeva uključuje GABA-ergički sustav

Novel Thiazolidinone-Azole Hybrids: Design, Synthesis and Antimycobacterial Activity Studies

Abstract To develop novel antimycobacterial agents, a new series of thiazolidinone-azole hybrids 4a-b, 5a-b and 6-13 were designed and synthesized. Thiazolidin-4-ones (4a-b and 5a-b) were obtained by the reaction of Schiff bases and hydrazones (2a-b and 3a-b) with mercaptoacetic acid. 5-Benzylidene derivatives (6-13) were gained by treatment of 5a-b with appropriate benzaldehydes according to Knoevenagel condensation. To evaluate their structures 1 H NMR, IR, mass spectrometry and elemental analysis data were used. The target compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv strain using the microplate alamar blue assay method. Among them, 6, 10 and 12 (MIC: 14.27-14.74 μM) were found as most active compounds in the series. It was seen that both phenylamino and benzylidene substitutions on thiazolidin-4-one ring caused an improvement in the antimycobacterial activity

Inhibition of Tyrosinase by 4H-Chromene Analogues: Synthesis, Kinetic Studies and Computational Analysis

Inhibition of mushroom tyrosinase was observed with synthetic dihydropyrano[3,2-b]chromenediones. Among them, DHPC04 displayed the most potent tyrosinase inhibitory activity with a Ki value of 4μM, comparable to the reference standard inhibitor kojic acid. A kinetic study suggested that these synthetic heterocyclic compounds behave as competitive inhibitors for the L-DOPA binding site of the enzyme. Furthermore, molecular modeling provided important insight into the mechanism of binding interactions with the tyrosinase copper active site

Design and development of novel inhibitors for the treatment of latent tuberculosis

Objective/background: “The captain of all these men of death”, is the apt sobriquet for the age-old disease tuberculosis (TB). Despite the availability of many drugs, cases of increasing resistance in the forms of multi-drug and extensively drug-resistant TB and persistence [characteristic of Mycobacterium tuberculosis (MTB)] make the eradication of TB a nightmare. Approval of bedaquiline by the Food and Drug Administration focused attention on quinoline scaffolds for development of new anti-TB agents. Lysine ɛ-aminotransferase (LAT) in MTB plays a pivotal role in regulating amino acid synthesis, which in turn affects mycobacterial persistence. Here, developed quinoline inhibitors that targeted LAT with an objective to eliminate dormant forms of mycobacterium. Methods: Using e-pharmacophore approaches, quinolone (PBD: 2CJD) leads were found to inhibit lysine binding to LAT. To investigate structural activity relationships, 21 analogues were synthesized and characterized based on the identified lead molecules. Results: Among the derivatives, N-(pyridin-2-yl methyl)-2-(4-(quinolin-4-yl) piperazin-1-yl) acetamide was identified as a potent molecule, with an IC50 for LAT of 1.04 μM. In nutrient-starved and zebra fish models, this molecule exhibited logarithmic reductions of 2.1- and 2.2-fold, respectively, at a concentration of 10 μg/mL. The compound also exhibited good activity against persistent forms of mycobacteria (biofilm model), showing logarithmic reduction of 2.8-fold. Additionally, the hit molecule showed concentration-dependent kill kinetics against dormant forms of mycobacteria, and were devoid of cytotoxicity against RAW cell lines 264.7 at concentrations of 50 μM. Conclusion: Our results indicated that the hit molecule showed activity against both active and persistent forms of infection, which is ideal for new anti-TB agents. This molecule requires further pharmacokinetic and dynamic screening for development as new drug candidate

Identification and development of novel indazole derivatives as potent bacterial peptidoglycan synthesis inhibitors

Background: Tuberculosis is well-known airborne disease caused by Mycobacterium tuberculosis. Available treatment regimen was unsuccessful in eradicating the deaths caused by the disease worldwide. Owing to the drawbacks such as prolonged treatment period, side effects, and drug tolerance, there resulted in patient noncompliance. In the current study, we attempted to develop inhibitors against unexplored key target glutamate racemase. Methods: Lead identification was done using thermal shift assay from in-house library; inhibitors were developed by lead derivatization technique and evaluated using various biological assays. Results: In indazole series, compounds 11 (6.32 ± 0.35 μM) and 22 (6.11 ± 0.51 μM) were found to be most promising potent inhibitors among all. These compounds also showed their inhibition on replicating and nonreplicating bacteria. Conclusion: We have developed the novel inhibitors against M. tuberculosis capable of inhibiting active and dormant bacteria, further optimization of inhibitor derivatives can results in better compounds for eradicating tuberculosis