Synthesis and antitubercular activity of monocyclic nitroimidazoles: insights from econazole

We have designed and synthesized econazole-derived nitroimidazoles to investigate the antitubercular activity of the nitroimidazole compounds. The introduction of a nitro group at the 4-position of the imidazole on econazole abolished the antitubercular activity. However, alcoholic nitroimidazoles 4 and 6 compounds were active against Mycobacterium tuberculosis (Mtb). While the MIC value of econazole was 16 μg/mL, the MIC of 6a and 6f turned out to be 0.5 μg/mL. In particular, the activity of 6f against non-replicating Mtb was as good as PA-824, which is currently in clinical phase II studies as an antitubercular agent. Overall, alcohol compounds 4 and 6 tend to be more active than ether compounds 5 and 7.     

Novel isoniazid embedded triazole derivatives: Synthesis,antitubercular and antimicrobial activity evaluation

In the present study, a series of new isoniazid embedded triazole derivatives have been synthesized. These compounds were evaluated for their in vitro antitubercular and antimicrobial activities. Among the screened compounds, six have exhibited potent antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC value 0.78 μg/mL, whereas, three compounds have displayed activity with MIC value ranging from 1.56 to 3.125 μg/mL. The cytotoxicity of the active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed even at 25 μg/mL concentration. The five compounds have displayed good antimicrobial activities. Molecular docking have been performed against mycobacterial InhA enzyme to gain an insight into the plausible mechanism of action which could pave the way for our endeavor to identify potent antitubercular candidates. We believe that further optimization of these molecules may lead to potent antitubercular agents.     

Rational design,synthesis and antitubercular evaluation of novel 2-(trifluoromethyl)phenothiazine-[1,2,3]triazole hybrids

Molecular hybridization is an emerging structural modification tool to design molecules with better pharmacophoric properties. A series of novel 2-(trifluoromethyl)phenothiazine-1,2,3-triazoles 5a–v designed by hybridizing two antitubercular drugs trifluoperazine and I-A09 in a single molecular architecture, were synthesized in very good yields using click chemistry. Among the all ‘22’ compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (Mtb), three analogs 5c, 5l and 5o were found to be most potent (MIC: 6.25 μg/mL) antitubercular agents with good selectivity index.     

Identification of a novel pyrrole derivative endowed with antimycobacterial activity and protection index comparable to that of the current antitubercular drugs streptomycin and rifampin

A hit optimization procedure based on isosteric and bioisosteric replacement of decorating groups at both the N1 and the C5 phenyl rings of 1,5-diarylpyrroles led to identification of 4-((1-(4-fluorophenyl)-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thiomorpholine that is characterized by a very high activity toward both Mycobacterium tuberculosis 103471 and H37Rv strains (MIC values of 0.125μg/mL), and a safe profile in terms of cytotoxicity (CC(50) of >128μg/mL) and protection index (>1000). Antitubercular activity and protection index of the new compound are comparable to those found for the current antitubercular drugs streptomycin and rifampin.     

Synthesis and antibacterial studies of binaphthyl-based tripeptoids. Part 2

A compact synthesis of 15 new binaphthyl-based dicationic tripeptoids and one biphenyl based dicationic tripeptoid is described. Fourteen of these tripeptoids resulted from variation of the C-2′ ether substituent of the binaphthyl unit. An O-iso-butyl ether binaphthyl derivative was found to be the most active against Staphylococcus aureus (MIC 1.95 μg/mL). The biphenyl analogue also showed good activity against S. aureus (MIC 1.95 μg/mL). These compounds, however, were less active against four vancomycin-resistant strains of enterococci (VRE) than some of our previously developed compounds that had an O-iso-pentyl ether substituent on the binaphthyl unit and a C-2 l-Leu moiety.     

Synthesis,screening and docking analysis of hispolon analogs as potential antitubercular agents

A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6 μg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25 μg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6 μg/mL) followed by H13 (6.25 μg/mL) and H17 (12.5 μg/mL), H19 (3.125 μg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and β-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH.     

Novel imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents

The increase in the prevalence of multi drug-resistant and extensively drug-resistant strains of Mycobacteriumtuberculosis case demonstrates the urgent need of discovering new promising compounds with antimycobacterial activity. As part of our research program and with a aim of identifying new antitubercular drug candidates, a new class of 2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazole derivatives has been synthesized by both conventional as well as microwave assisted method and evaluated for their in vitro antitubercular activity against M. tuberculosis H(37)Rv. Moreover, various drug-likeness properties of new compounds were predicted. Seven compounds from the series exhibited good activity with MIC in range 3.12-1.56μg/ml. The present study suggests that compounds 6b, 6c, 6d, 6e and 6f may serve as promising lead scaffolds for further generation of new anti-TB agents.     

Synthesis and antimycobacterial evaluation of various 6-substituted pyrazolo[3,4-d]pyrimidine derivatives

Various pyrazolo[3,4-d]pyrimidines carrying a variety of substituents in the 6-position have been synthesised and their ability to inhibit growth of Mycobacterium tuberculosis in vitro has been determined. Compounds 5a, 5b, 6c, 7a, 7b, 8d, 8e and 8f demonstrated a minimum inhibitory concentration (MIC) of <6.25?μg/mL and were found to be active against Mycobacterium tuberculosis strain H(37)RV. Compound 8d was found to be the most active compound in vitro with a MIC of <6.25?μg/mL and inhibitory concentration IC(90) of 1.53?μg/mL.     

Design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates

We report herein the design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates based on the structure of SB-222734. The antibacterial activities of these newly synthesized compounds were also evaluated and compared with linezolid and retapamulin. Results showed that most of the target compounds exhibit good potency in inhibiting the growth of Gram-positive bacteria including Methicillin-susceptible Staphylococcus aureus MSSA (MIC: 0.0625-2μg/mL), Methicillin-resistant S. aureus MRSA (MIC: 0.0625-2μg/mL), Methicillin-susceptible Staphylococcus epidermidis MSSE (MIC: 0.0625-2μg/mL), Methicillin-resistant S. epidermidis MRSE (MIC: 0.0625-2μg/mL), and Streptococcus pneumonia (MIC: 0.0625-4μg/mL). In particular, three remarkable compounds of this series (12l, 12m, and 21l) exhibited comparable in vitro antibacterial profiles to that of retapamulin.     

Synthesis of novel 3-cyclohexylpropanoic acid-derived nitrogen heterocyclic compounds and their evaluation for tuberculostatic activity

A series of novel 3-cyclohexylpropanoic acid derivatives and 3-cyclohexylpropanoic acid-derived nitrogen heterocyclic compounds (1-8) have been synthesized and evaluated for tuberculostatic activity. Compounds 1a, 1c, 1e and 1f bearing benzimidazole or benzimidazole-like systems showed the most potent tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 1.5 to 12.5μg/mL. More importantly 1a (6-chloro-2-(2-cyclohexylethyl)-4-nitro-1H-benzo[d]imidazole) and 1f (2-(2-cyclohexylethyl)-1H-imidazo[4,5-b]phenazine) appeared selective for M. tuberculosis as compared with eukaryotic cells (human fibroblasts), and other antimicrobial strains. These compounds may thus represent a novel, selective class of antitubercular agents. Additionally compound 1a stimulated type I collagen output by fibroblasts, in vitro.     

Tuberculosis: finding a new potential antimycobacterium derivative in a aldehyde-arylhydrazone-oxoquinoline series

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis, which remains a serious public health problem. The emergence of resistant bacterial strains has continuously increased and new treatment options are currently in need. In this work, we identified a new potential aldehyde-arylhydrazone-oxoquinoline derivative (4e) with interesting chemical structural features that may be important for designing new anti-TB agents. This 1-ethyl-N'-[(1E)-(5-nitro-2-furyl)methylene]-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (4e) presented an in vitro active profile against M. tuberculosis H37Rv strain (minimum inhibitory concentration, MIC?=?6.25?μg/mL) better than other acylhydrazones described in the literature (MIC?=?12.5?μg/mL) and close to other antitubercular agents currently on the market. The theoretical analysis showed the importance of several structural features that together with the 5-nitro-2-furyl group generated this active compound (4e). This new compound and the analysis of its molecular properties may be useful for designing new and more efficient antibacterial drugs.     

Synthesis and antitubercular activity of heterocycle substituted diphenyl ether derivatives

Despite being an ancient disease, tuberculosis (TB) remains the leading single-agent infectious disease killer in the world. The emerging serious problem of TB control and clinical management prompted us to synthesize a novel series of heterocyclic substituted diphenyl ether derivatives and determine their activity against the H37Rv strain of Mycobacterium. All ten compounds inhibited the growth of the H37Rv strain of Mycobacterium at concentrations of 1 μg/mL. This activity was found to be comparable to the reference drugs rifampicin and isoniazid at the same concentration. While the antimicrobial activity of other diphenyl ether analogues, such as triclosan, is associated with the inhibition of enoyl-ACP reductase (ENR), the synthesised substituted diphenyl ether derivatives did not affect this enzyme activity in spite of their structural similarity with triclosan. Therefore, these compounds appear to have a novel mechanism of action against M. tuberculosis, and their structural features should be studied further for their potential as new antitubercular drugs.     

3-[Benzimidazo- and 3-[benzothiadiazoleimidazo-(1,2-c)quinazolin-5-yl]-2H-chromene-2-ones as potent antimicrobial agents

A series of 3-[benzimidazo(1,2-c)quinazolin-5-yl]-2H-chromene-2-one (6a-6f) and 3-[benzothiadiazole- imidazo(1,2-c)quinazolin-5-yl]-2H-chromene-2-one derivatives (7a-7f) that incorporate a variety of substituents at the 6- and/or 8-positions of the coumarin moieties have been synthesized utilizing cellulose sulfuric acid as an efficient catalyst under both conventional heating and microwave irradiation procedures. These analogs were evaluated for their antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Streptococcus pyogenes (Gram-positive bacteria), Escherichia Coli, Klebsiella pneumonia, Salmonella typhimurium (Gram-negative bacteria), and Aspergillus niger, Candida albicans, and Aspergillus flavus (Fungi). Two analogs, 6c (a 6,8-dichloro analog, MIC([SA]) = 2.5 μg/mL; MIC([ST]) = 2.5 μg/mL) and 7d (a 6,8-dibromo analog, MIC([ST]) = 2.5 μg/mL) were identified as potent antibacterial agents, and two analogs, 6b (a 6-bromo analog, MIC([AF]) = 10 μg/mL) and 6d (a 6,8-dibromo analog, MIC([AF]) = 15 μg/mL; MIC([CA]) = 15μg/mL), were identified as potent antifungal agents. Based on the MIC data, analogs 6b, 6c, 6d, and 7d were identified as the most potent antimicrobial agents in the series.     

Novel dihydropyrimidines as a potential new class of antitubercular agents

A small library of 30 dihydropyrimidines was synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Rv. Two compounds, ethyl 4-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylate 4a and ethyl 4-[3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 4d were found to be the most active compounds in vitro with MIC of 0.02 μg/mL against MTB and were more potent than isoniazid.     

Synthesis,characterization and in vitro biological evaluation of some novel 1,3,5-triazine–Schiff base conjugates as potential antimycobacterial agents

A series of some novel 1,3,5-triazine–Schiff base conjugates (1–32) have been synthesized and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using Alamar Blue assay and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Compounds 4 (4-Methoxy-6-methyl-N-(3,4,5-trimethoxybenzylidene)-1,3,5-triazin-2-amine), 11 (4-Methoxy-6-methyl-N-(2-hydroxy-3-bromo-5-chloro-benzylidene)-1,3,5-triazin-2-amine) and 24 (4-Methoxy-6-methyl-N-(1-(2,5-dihydroxyphenyl)ethylidene)-1,3,5-triazin-2-amine) exhibited a significant activity at 3.125, 6.25 and 6.25 μg/mL, respectively, when compared with the antitubercular drugs such as ethambutol (3.125 μg/mL), pyrazinamide (6.25 μg/mL) and streptomycin (6.25 μg/mL) and it could be a potential starting point to develop new lead compounds in the fight against Mycobacterium tuberculosis H37Rv.     

1-Chloro-2-formyl indenes and tetralenes as antitubercular agents

1-Chloro-2-formyl indenes and tetralenes have been synthesized using Vilsmeier-Haack-Arnold reaction onto indanones and tetralones. Most of these analogues exhibited antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MICs ranging from 30 to 500 μg/mL. Analogue 13 was further modified to some derivatives. The most active analogue 23 showing MIC at 30 μg/mL was further evaluated for acute oral toxicity in Swiss albino mice and was found to be safe up to 300 mg/kg dose.     

Synthesis, molecular modeling and bio-evaluation of cycloalkyl fused 2-aminopyrimidines as antitubercular and antidiabetic agents

An economical and efficient one step synthesis of a series of 8-(arylidene)-4-(aryl)-5,6,7,8-tetrahydro-quinazolin-2-ylamines and 9-(arylidene)-4-(aryl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-2-ylamines by the reaction of bis-benzylidene cycloalkanones and guanidine hydrochloride in presence of NaH has been developed. All the synthesized compounds were evaluated against Mycobacterium tuberculosis H₃₇Rv strain and the α-glucosidase and glycogen phosphorylase enzymes. Few of the compounds have shown interesting in vitro activity with MIC up to 3.12 μg/mL against M. tuberculosis and very good inhibition of α-glucosidase and glycogen phosphorylase enzymes. The most potent non toxic compound 40 exhibited about 58% ex vivo activity at MIC of 3.12 μg/mL. The present study opens a new gate to synthesize antitubercular agents for diabetic TB patients. In silico docking studies indicate that mycobacterial dihydrofolate reductase is the possible target of these compounds.     

特比萘芬对24株黑酵母样真菌的体外药敏试验研究

目的 评价特比萘芬对7个属24株刺盾霉目（Chaetothyriales）黑酵母样真菌体外敏感性.方法 应用美国国家临床和实验室标准研究所（CLSI）的M38-A2方案.菌悬液终浓度为（0.4 ～5）＆#215;104 CFU/mL,30℃孵育5～7d,测定最低有效浓度（MEC）和最低抑菌浓度（MIC）.结果 特比萘芬对24株黑酵母样真菌MEC范围：0.125 ～4μg/mL,MEC90∶2μg/mL,MEC50∶0.25 μg/mL,GM∶0.392 9 μg/mL,特比萘芬对5株暗色真菌100％生长抑制,MIC范围：1～4 μg/mL,MIC50∶2μg/mL,MIC90∶4μg/mL.结论 特比萘芬对刺盾霉目（Chaetothyriales）中的黑酵母样真菌有较强的抑制作用,50％抑菌作用明显.     

Synthesis and evaluation of antitubercular activity of glycosyl thio- and sulfonyl acetamide derivatives

A series of glycosyl thioacetamide and glycosyl sulfonyl acetamide derivatives have been prepared following a convenient reaction protocol and evaluated for their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv. Amongst 32 compounds evaluated 3 compounds were effective in inhibiting mycobacterial growth at MIC of 6.25 μg/mL, 6 compounds at MIC of 3.125 μg/mL and 1 compound at MIC of 1.56 μg/mL. All active compounds were found nontoxic in Vero cell lines and mice bone marrow macrophages.     

Design,synthesis and in vivo/in vitro screening of novel chlorokojic acid derivatives

A series of novel Mannich bases of chlorokojic acid (2-chloromethyl-5-hydroxy-4H-pyran-4-one) were synthesized and their biological activities were investigated. Anticonvulsant activity results according to phase-I tests of Antiepileptic Drug Development (ADD) Program revealed that compound 13 was the most effective one at 4?h against subcutaneous pentylenetetrazole (scPTZ)-induced seizure test. Antimicrobial activities were evaluated in vitro against bacteria and fungi by using broth microdilution method. The antitubercular activities against Mycobacterium tuberculosis and M. avium were discussed with Resazurin microplate assay (REMA). The antimicrobial activity results indicated that compounds 1 and 12 (MIC: 8–16 µg/mL) showed higher activity against Gram negative bacteria while compound 12 had MIC: 4–16 µg/mL against Gram positive bacteria. Compound 1 was the most active one with MIC values of 8–32 µg/mL against fungi. Mannich bases also exhibit significant antitubercular activity in a MIC range of 4 to 32 µg/mL, especially compound 18 against M. avium.