Rational drug design based synthesis of novel arylquinolines as anti-tuberculosis agents

A series of novel arylquinoline derivatives was designed retaining significant pharmacophoric features and three dimensional geometry of bedaquiline. In silico ADME study was performed to assess drug likeness and toxicity profiles of the designed molecules. The compounds were evaluated for activity against Mycobacterium tuberculosis H₃₇Rv using Resazurin Microtitre Assay (REMA) plate method and cytotoxicity in VERO C1008 cell line. Several of the synthesized compounds exhibited good antituberculosis activity and selectivity, especially compounds, 12i (MIC: 5.18 μM and MIC/CC₅₀: 152.86) and 12l (MIC: 5.59 μM and MIC/CC₅₀: 160.57). The study opens up a new platform for the development of arylquinoline based drugs for treating tuberculosis.     

A regio- and stereoselective 1,3-dipolar cycloaddition for the synthesis of new-fangled dispiropyrrolothiazoles as antimycobacterial agents

A series of dispiropyrrolothiazoles compounds were synthesized using 1,3-dipolar cycloaddition and were screened for antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv and INH resistant M. tuberculosis strains. Two of them were showing good activity with MIC of less than 1 μM. Compound (5f) was found to be the most active with MIC of 0.210 and 8.312 μM respectively.     

Antitubercular activity of quinolizidinyl/pyrrolizidinylalkyliminophenazines

Novel riminophenazine derivatives, characterized by the presence of the basic and cumbersome quinolizidinylalkyl and pyrrolizidinylethyl moieties, have been synthesized and tested (Rema test) against Mycobacterium tuberculosis H₃₇R_v and H₃₇R_a, and six clinical isolates of Mycobacterium avium and Mycobacterium tuberculosis. Most compounds exhibited potent activity against the tested strains, resulting more active than clofazimine, isoniazid and ethambutol.The best compounds (4, 5, 12 and 13) exhibited a MIC in the range 0.82–0.86 μM against all strains of Mycobacterium tuberculosis and, with the exception of 4 a MIC around 3.3 μM versus M. avium. The corresponding values for clofazimine (CFM) were 1.06 and 4.23 μM, respectively. Cytotoxicity was evaluated against three cell lines and compound 4 displayed a selectivity index (SI) versus the human cell line MT-4 comparable with that of CFM (SI = 5.23 vs 6.4). Toxicity against mammalian Vero 76 cell line was quite lower with SI = 79.     

Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes

In this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8–13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25 μg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC₉₀ <1 μg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10–50% or even more (10b) under experimental conditions.     

Anti-tubercular agents. Part 8: Synthesis,antibacterial and antitubercular activity of 5-nitrofuran based 1,2,3-triazoles

A series of 5-nitrofuran–triazole conjugates were synthesized and evaluated for their antimicrobial activity against both Gram-positive and Gram-negative bacterial strains. All the compounds exhibited promising inhibition towards Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 8a, 8b, 8e, 8f, 8h are most active among the series exhibiting MIC value of 1.17 μg/ml against different bacterial strains. The bactericidal activity is found to be in accordance with the bacterial growth inhibition data. Compound 8e was found to be equipotent to the standard drug Ciprofloxacin displaying MBC value of 1.17 μg/ml against the bacterial strain Bacillus subtilis. The compounds have also demonstrated promising antibacterial activity against the resistant strain MRSA and were found to be effective inhibitors of biofilm formation. The compound 8b exhibited excellent anti-biofilm activity with IC₅₀ value as low as 0.8 μg/ml. These conjugates were also screened for antitubercular activity against Mycobacterium tuberculosis H₃₇Rv strain. Compound 8e showed promising antitubercular activity with MIC value of 0.25 μg/ml. Most of these compounds are less toxic to normal mammalian cells than the widely used antibacterial drug Ciprofloxacin.     

A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents

A series of fourteen dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 μM. Compound 4′-(4-bromophenyl)-1′-methyldispiro[acenaphthylene-1,2′-pyrrolidine-3′,2″-indane]-2,1″(1H)-dione (4c) was found to be the most active with MIC of 12.50 μM.     

Substituted hydrazinecarbothioamide as potent antitubercular agents: Synthesis and quantitative structure–activity relationship (QSAR)

A series of novel substituted hydrazinecarbothioamides was synthesized and evaluated for anti-TB activity. Three most active compounds viz. 1, 6 and 12 were found to exhibit minimum inhibitory concentration (MIC) of 0.4 μg/mL, whereas four compounds viz. 3, 5, 10 and 11 showed comparatively lesser activity with MIC value of 0.8 μg/mL against Mycobacterium tuberculosis strain. A highly significant QSAR equation explaining 81.8% variance is described.     

Design,synthesis and evaluation of 6-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenanthridine analogues as antimycobacterial agents

Focus in this Letter is made to design and synthesize a series of nineteen new 6-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenanthridine analogues employing click chemistry and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H₃₇Rv. Among the tested compounds, 7f and 7j exhibited good activity (MIC = 3.125 μg/mL), while 8a displayed excellent activity (MIC = 1.56 μg/mL) against the growth of M. tuberculosis H₃₇Rv. In addition, 7f, 7j and 8a compounds were subjected to cytotoxic studies against mouse macrophage (RAW264.7) cell lines and the selectivity index values are >15 indicating suitability of compounds for further drug development.     

Design,synthesis and biological evaluation of imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole derivatives as Mycobacterium tuberculosis pantothenate synthetase inhibitors

In the present study, we have designed imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole derivatives from earlier reported imidazo[1,2-a]pyridine based Mycobacterium tuberculosis (MTB) pantothenate synthetase (PS) inhibitors. We synthesized thirty compounds and they were evaluated for MTB PS inhibition study, in vitro anti-TB activities against replicative and non-replicative MTB, in vivo activity using Mycobacterium marinum infected Zebra fish and cytotoxicity against RAW 264.7 cell line. Among them compound 2-methyl-N′-(4-phenoxybenzoyl)benzo[d]imidazo[2,1-b]thiazole-3-carbohydrazide (5bc) emerged as potent compound active against MTB PS with IC₅₀ of 0.53 ± 0.13 μM, MIC of 3.53 μM, 2.1 log reduction against nutrient starved MTB, with 33% cytotoxicity at 50 μM. It also showed 1.5 log reduction of M. marinum load in Zebra fish at 10 mg/kg.     

A new benzoic acid derivative from Piper diospyrifolium and its anti-Mycobacterium tuberculosis activity

The extraction by supercritical fluid (SFE-CO₂) from leaves of Piper diospyrifolium and chromatographic column purification afforded the isolation of a new benzoic acid derivative 4-methoxy-3-[(E)-3-methyl-1,3-butadien-1-yl]-5-(3-methyl-2-buten-1-yl)-benzoic acid (1). The chemical structure was elucidated on the basis of spectroscopic methods and comparison with literature data. SFE-CO₂ extracts and (1) were tested for their anti-Mycobacterium tuberculosis activities and cytotoxicities in J774G.8 macrophages. The compound (1) and SFE-CO₂ extracts exhibited moderate activities against M. tuberculosis H₃₇Rv with minimum inhibitory concentration (MIC) values of 125 μg/mL. The MIC values of M. tuberculosis clinical isolates ranged from 125 μg/mL to >250 μg/mL. The cytotoxicities results showed a selectivity index range from 0.6 to 1.0. Additional studies in structure activity-relationship as well as synergistic activity with antituberculous drugs should be conducted for a better evaluation of anti-mycobacterial activity of this compound.     

Synthesis and antimycobacterial evaluation of pyrazinamide derivatives with benzylamino substitution

A series of 19 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro whole cell antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two types of Mycobacterium avium. The series consisted of 3-(benzylamino)-5-cyanopyrazine-2-carboxamides and 3-(benzylamino)pyrazine-2,5-dicarbonitriles with various substituents on the phenyl ring. RP-HPLC method was used to determine the lipophilicity of the prepared compounds. Nine compounds exerted similar or better activity against Mycobacterium tuberculosis compared to pyrazinamide (MIC = 6.25–12.5 μg/mL). 3-(Benzylamino)pyrazine-2,5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12.5–25 μg/mL. Although not the most active, 4-NH₂ substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI = 5.5 and SI >21.     

Synthesis and in vitro antitubercular activity of a series of quinoline derivatives

A series of 33 quinoline derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H₃₇Rv using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Compounds 5e and 5f exhibited a significant activity at 6.25 and 3.12 μg/mL, respectively, when compared with first line drugs such as ethambutol and could be a good starting point to develop new lead compounds in the fight against multi-drug resistant tuberculosis.     

Identification and development of 2-methylimidazo[1,2-a]pyridine-3-carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors

In the present study, we used crystal structure of mycobacterial pantothenate synthetase (PS) bound with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl) acetic acid inhibitor for virtual screening of antitubercular compound database to identify new scaffolds. One of the identified lead was modified synthetically to obtain thirty novel analogues. These synthesized compounds were evaluated for Mycobacterium tuberculosis (MTB) PS inhibition study, in vitro antimycobacterial activities and cytotoxicity against RAW 264.7 cell line. Among the compounds tested, N′-(1-naphthoyl)-2-methylimidazo[1,2-a]pyridine-3-carbohydrazide (5b) was found to be the most active compound with IC₅₀ of 1.90 ± 0.12 μM against MTB PS, MIC of 4.53 μM against MTB with no cytotoxicity at 50 μM. The binding affinity of the most potent inhibitor 5b was further confirmed biophysically through differential scanning fluorimetry.     

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.     

Secondary metabolites from the root of Ehretia longiflora and their biological activities

Bioassay-guided fractionation of the methanolic extract of the root of Ehretia longiflora (Boraginaceae) afforded eight compounds, ehretiquinone (1), ehretiolide (2), ehreticoumarin (3), ehretilactone A (4), ehretilactone B (5), ehretiamide (6), ehretine (7), and ehretiate (8), together with 12 known compounds (9–20). The relative configuration of 1 was determined by single crystal X-ray diffraction. Among the isolates, 1 and prenylhydroquinone (14) showed antitubercular activity against Mycobacterium tuberculosis strain H37Rv with MIC values of 25.0 and 26.2 μg/mL, respectively. Moreover, 1 exhibited inhibitory effects on N-formylmethionylleucylphenylalanine (fMLP)-induced superoxide production, with IC₅₀ value of 0.36 ± 0.03 μM.     

Synthesis and in vitro anti Mycobacterium tuberculosis activity of a series of phthalimide derivatives

New phthalimide derivatives were easily prepared through condensation of phthalic anhydride and selected amines with variable yields (70–90%). All compounds (3a–l) were evaluated against Mycobacterium tuberculosis H₃₇Rv using Alamar Blue susceptibility. The compounds 3c, 3i, and 3l have the minimum inhibitory concentrations (MICs) of 3.9, 7.8, and 5.0 μg/mL, respectively, and could be considered new lead compounds in the treatment of tuberculosis and multi-drug resistant tuberculosis.     

Design,synthesis, and biological evaluation of 4-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives as potent antitubercular agents

Based on stereoelectronic feature analysis using density functional theory (DFT) at B3LYP/3-211G level, a series of 4-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives with low LUMO energies (<?0.10 eV); concentrated over the nitro group, furan moiety and α,β-unsaturated carbonyl bridge were envisaged as potential antitubercular agents. The target compounds were prepared by condensation of 5-nitro-2-furaldehyde with various ketones under acidic condition. The compounds were evaluated for antitubercular activity against Mycobacterium tuberculosis H37Rv and their cytotoxicity in VERO cell line. Several synthesized compounds showed good antitubercular activity of <5 μM along with low cytotoxicity. In particular, compound ((E)-3-(5-nitrofuran-2-yl)-1-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one) (3v) was found to be very potent (MIC: 0.19 μM) with good selectivity index (MIC₉₀/CC₅₀: >1800). Thus, this study shows the potential of stereoelectronic property analysis in developing improved nitroaromatics as antitubercular agents.     

Simple dihydrosphyngosine analogues with potent activity against MDR-Mycobacterium tuberculosis

Fifteen dihydrosphingosine analogues have been synthesized and tested in vitro against Mycobacterium tuberculosis (MTB). Two ether (3 and 4b) and one diamine (8b) derivatives have displayed high mycobactericidal potency, with similar MIC values of 1.25 μg/mL, against the virulent strain H37Rv, as well as against a clinical isolate resistant to the five first-line anti-TB drugs. The three compounds, tested on other eleven cultured MTB strains with different multi-drug-resistance (MDR) patterns, retained their MIC values for most strains, or even lowered it, as in the case of compound 4b, which, assayed on strain No. 332, also resistant to all first-line anti-TB drugs, attained the MIC value of 0.78 μg/mL.     

Salicylanilide diethyl phosphates: Synthesis,antimicrobial activity and cytotoxicity

A series of 27 salicylanilide diethyl phosphates was prepared as a part of our on-going search for new antimicrobial active drugs. All compounds exhibited in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium strains, with minimum inhibitory concentration (MIC) values of 0.5–62.5 μmol/L. Selected salicylanilide diethyl phosphates also inhibit multidrug-resistant tuberculous strains at the concentration of 1 μmol/L. Salicylanilide diethyl phosphates also exhibited mostly the activity against Gram-positive bacteria (MICs ⩾1.95 μmol/L), whereas their antifungal activity is significantly lower. The IC₅₀ values for Hep G2 cells were within the range of 1.56–33.82 μmol/L, but there is no direct correlation with MICs for mycobacteria.     

In vitro growth inhibitory effects of 13,28-epoxyoleanane triterpene saponins in cancer cells

Two new 13,28-epoxyoleanane triterpene saponins, magnosides A (1) and B (2), were isolated from the 95% ethanolic extract of Cybianthus magnus (Mez) Pipoly roots. Their structures were deduced by a combination of spectral analyses and chemical evidences as compared to data reported in the literature. The hemolytic activity of both compounds was measured. Compound 1 was shown to exhibit the strongest hemolytic activity with a HD₅₀ of 3.8 μM followed by 2 with a HD₅₀ of 33.5 μM. The bioactivity of compounds 1 and 2 was also evaluated in vitro against different cellular models including Mycobacterium tuberculosis, Leishmania amazonensis axenic amastigotes, mouse peritoneal macrophages and eight cancer cell lines. While neither of the tested compounds displayed any activity against M. tuberculosis, both exhibited anti-leishmanial activity against axenic amastigotes as well as in vitro growth inhibitory activity against all tested cancer cell lines with IC₅₀ growth inhibitory concentrations ranging between 4 μM and 33 μM. The compounds displayed similar growth inhibitory activity in cancer cell lines sensitive to pro-apoptotic stimuli versus those displaying various levels of resistance to such stimuli. Quantitative videomicroscopy analyses revealed that compounds 1 and 2 are cytotoxic.