Synthesis and antimycobacterial properties of N-substituted 6-amino-5-cyanopyrazine-2-carboxamides

A series of fifteen new compounds related to pyrazinamide (PZA) were synthesized, characterized with analytical data and screened for antimycobacterial, antifungal and antibacterial activity. The series consists of 6-chloro-5-cyanopyrazine-2-carboxamide and N-substituted 6-amino-5-cyanopyrazine-2-carboxamides, derived from the previous by nucleophilic substitution with various non-aromatic amines (alkylamines, cycloalkylamines, heterocyclic amines). Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis equal to pyrazinamide (12.5-25 μg/mL). More importantly, 6-chloro-5-cyanopyrazine-2-carboxamide and 5-cyano-6-(heptylamino)pyrazine-2-carboxamide were active against Mycobacterium kansasii and Mycobacterium avium, which are unsusceptible to PZA. Basic structure-activity relationships are presented. Only weak antifungal and no antibacterial activity was detected.     

Synthesis and structure activity relationship of imidazo[1,2-a]pyridine-8-carboxamides as a novel antimycobacterial lead series

Imidazo[1,2-a]pyridine-8-carboxamides as a novel antimycobacterial lead were generated by whole cell screening of a focused library against Mycobacterium tuberculosis. Herein, we describe the synthesis and structure activity relationship evaluation of this class of inhibitors and the optimization of physicochemical properties. These are selective inhibitors of Mycobacterium tuberculosis with no activity on either gram positive or gram negative pathogens.     

Alkylamino derivatives of pyrazinamide: Synthesis and antimycobacterial evaluation

A series of pyrazinamide derivatives with alkylamino substitution was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial, bacterial and fungal strains. The target structures were prepared from the corresponding 5-chloro (1) or 6-chloropyrazine-2-carboxamide (2) by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines). To determine the influence of alkyl substitution, corresponding amino derivatives (1a, 2a) and compounds with phenylalkylamino substitution were prepared. Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis H37Rv significantly better than standard pyrazinamide and corresponding starting compounds (1 and 2). Basic structure–activity relationships are presented. Only weak antibacterial and no antifungal activity was detected.     

Design,synthesis and antimycobacterial activity evaluation of natural oridonin derivatives

In an effort to develop novel potent antitubercular drugs, thirty-one oridonin derivatives were designed and prepared. All the compounds obtained were screened for their in vitro activities against Mycobacterium phlei, Mycobacterium smegmatis and Mycobacterium marinum. Among them, thirteen compounds showed significant inhibitory activity against M. phlei with MICs less than 2 μg/mL. Compounds 2k, 8d, 10c, 10d containing trans-cinnamic acid moiety were the most potent (MIC = 0.5 μg/mL), comparable to the well-known antitubercular drug streptomycin. The preliminary structure–activity relationships (SARs) were also analyzed.     

Synthesis and biological evaluation of 2-aminothiazole derivatives as antimycobacterial and antiplasmodial agents

A series of compounds derived from the 2-amino-4-(2-pyridyl) thiazole scaffold was synthesized and tested for in vitro antimycobacterial activity against the Mycobacterium tuberculosis H37Rv strain, antiplasmodial activity against the chloroquine sensitive NF54 Plasmodium falciparum strain and cytotoxicity on a mammalian cell line. Optimal antimycobacterial activity was found with compounds with a 2-pyridyl ring at position 4 of the thiazole scaffold, a substituted phenyl ring at the 2-amino position, and an amide linker between the scaffold and the substituted phenyl. The antiplasmodial activity was best with compounds that had the phenyl ring substituted with hydrophobic electron withdrawing groups.     

Synthesis and antimycobacterial activities of some new thiazolylhydrazone derivatives

This Letter reports the synthesis and evaluation of some thiazolylhydrazone derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. The cytotoxic activities of all compounds were also evaluated. The compounds exhibited promising antimycobacterial activity with MICs of 1.03–72.46 μM and weak cytotoxicity (8.9–36.8% at 50 μg/mL). Among them, 1-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine 10 was found to be the most active compound (MIC of 1.03 μM) with a good safety profile (16.4% at 50 μg/mL). Molecular modeling studies were done to have an idea for the mechanism of the action of the target compounds. According the docking results it can be claimed that these compounds may bind most likely to TMPK than InhA or CYP121.     

Synthesis and antimycobacterial activity of novel camphane-based agents

A series of six new amidoalcohols was designed and synthesized on the base of the camphor scaffold. Natural amino acids were transformed into their α-hydroxy analogues with retention of configuration, and attached to isobornylamine. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. The activity shifts from micromolar to nanomolar inhibitory concentrations depending on the α-hydroxy acid moiety. Two of the most potent compounds exert low level of cytotoxic activity. These camphane-based amido-alcohols present promising potential lead compounds for further elaboration of antimycobacterial agents.     

Synthesis and antimycobacterial activity of isoniazid derivatives from renewable fatty acids

This work describes the synthesis of a series of fatty acid hydrazide derivatives of isoniazid (INH). The compounds were tested against Mycobacterium tuberculosis H37Rv (ATCC 27294) as well as INH-resistant (ATCC 35822 and 1896 HF) and rifampicin-resistant (ATCC 35338) M. tuberculosis strains. The fatty acid derivatives of INH showed high antimycobacterial potency against the studied strains, which is desirable for a pharmaceutical compound, suggesting that the increased lipophilicity of isoniazid plays an important role in its antimycobacterial activity.     

Synthesis and biological evaluation of sugar-derived chiral nitroimidazoles as potential antimycobacterial agents

Chiral nitroimidazoles were synthesized using sugars as the chiral source. The synthesized compounds showed promising antimycobacterial property with MIC value in the range 6.25–12.5 μg/mL against Mycobacterium tuberculosis H₃₇Rv.     

Synthesis and antimycobacterial evaluation of N-substituted 3-aminopyrazine-2,5-dicarbonitriles

A series of 14 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and two types of Mycobacterium avium. The series comprised of N-substituted 3-aminopyrazine-2,5-dicarbonitriles derived from 3-chloropyrazine-2,5-dicarbonitrile by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines, cycloalkylamines and heterocyclic amines). Noteworthy antimycobacterial activity against M. tuberculosis was found among the alkylamino derivatives, for example, 3-(heptylamino)pyrazine-2,5-dicarbonitrile inhibited M. tuberculosis at MIC=51 μmol/L. 3-(Hexylamino)pyrazine-2,5-dicarbonitrile inhibited M. kansasii at MIC=218 μmol/L. Basic structure-activity relationships are discussed. A comparison between calculated and experimentally determined lipophilicity parameters within the series is included.     

Synthesis and biological evaluation of N-(aryl)-2-thiophen-2-ylacetamides series as a new class of antitubercular agents

The present article describes a series of 21 N-(aryl)-2-thiophen-2-ylacetamides, which were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. The compounds 2, 3, 7, 8, 11, 12, 15, 16, and 20 exhibited activity between 25 and 100 μg/mL and could be a good start point to find new lead compounds in the fight against multidrug resistant tuberculosis.     

Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis

Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H₃₇Rv) strain and two isoniazid-resistant strains (INH_R1 and INH_R2) of Mycobacterium tuberculosis. The antimycobacterial activity of the derivatives was determined based on the resazurin microtiter assay and their cytotoxicity in adhered mouse monocyte macrophage J774.A1 cells (ATCC TIB-67). Of the twenty-two compounds evaluated against the three strains of M. tuberculosis, twenty-one presented some activity against the H₃₇Rv and INH_R1 (katG S315T) or INH_R2 (inhA C(−5)T) strains. Compounds 1a, 2a, and 8a were effective against the INH_R1 strain, and compounds 1a, 1b, 2a, 3a, 5a, 5b and 8a were effective against the INH_R2 strain, with MICs in the range of 3.12–6.25 µg/mL. Compounds 1b and 5b were the most active against H₃₇Rv, with MIC of 0.78 µg/mL. Based on the selectivity index, 1b and 5b can be considered safe as a drug candidate compounds. These results demonstrate that quinoidal compounds can be used as promising scaffolds for the development of new anti-TB drugs and hybrids with activity against M. tuberculosis-susceptible and INH-resistant strains.     

Synthesis,antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones

A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–g and coumarin containing hydrazide-hydrazone analogues 4a–e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28–1.69 μM, which were comparable to those of isoniazid. The cytotoxicity (IC₅₀ > 200 µM) to the “normal cell” model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–e, was noticeably milder compared to that of their hydrazone analogues 4a–e (IC₅₀ 33–403 µM). Molecular docking studies on compounds 4a–e and 5b–g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds.     

Unveiling the anticancer and antimycobacterial potentials of bioengineered gold nanoparticles

Synthesis of gold nanoparticles was carried out using Pongammia pinnata (pongam) leaf extract and their anticancer and antimycobacterial activities were studied. Gold nanoparticle formation was confirmed by UV–vis, XRD and HR-TEM. The anticancer efficacies of the biogenic gold nanoparticles were analyzed using cytotoxicity, cell morphology analysis, oxidative DNA damage, apoptosis detection and toxicity studies. Biogenic gold nanoparticles inhibited breast cancer cell line (MCF-7) proliferation with an efficacy of IC₅₀ of 1.85 μg/mL. The antimycobacterial potential of the biogenic gold nanoparticles was screened against M. tuberculosis by Luciferase Reporter Phage (LRP) assay. The gold nanoparticles showed inhibition against sensitive M. tuberculosis with the minimum inhibitory concentration (MIC) of 10 μg/mL whereas no inhibition was found against the rifampicin resistant M. tuberculosis.     

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.     

Synthesis and antimycobacterial activity of highly functionalized tetrahydro-4(1H)-pyridinones

A series of 35 2e,3e,6e-triaryltetrahydro-4(1H)-pyridinones, 2e,3e,5e,6e-tetraaryltetrahydro-4(1H)-pyridinones and their N-nitroso and N-cyano analogs have been prepared. All these 35 compounds obtained were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB). Among them, the N-nitrosopyridinones are found to be more active against MTB than the corresponding N-CN analogs, which, in turn, were slightly more active than NH analogs. In particular, the N-nitroso compounds, 3d, 4b and 4e with halogen-bearing phenyl rings at 2,6-positions showed maximum activity with MIC values of 3.97, 3.11 and 3.11 μM, being more efficacious than the first line anti-TB drugs, ciprofloxacin, ethambutol and pyrazinamide. A general trend has also been discerned in all the three classes of NH, N-CN and N-NO compounds, in each of which those bearing four aryl rings display higher activity than that having three analogously substituted aryl rings disclosing that lipophilicity could be an important factor underlying antimycobacterial activity.     

Synthesis,antimicrobial evaluation and molecular modeling of 5-hydroxyisoquinolinium salt series; the effect of the hydroxyl moiety

In the present paper, we describe the synthesis of a new group of 5-hydroxyisoquinolinium salts with different lengths of alkyl side-chain (C₁₀–C₁₈), and their chromatographic analysis and biological assay for in vitro activity against bacterial and fungal strains. We compare the lipophilicity and efficacy of hydroxylated isoquinolinium salts with the previously published (non-hydroxylated) isoquinolinium salts from the point of view of antibacterial and antifungal versatility and cytotoxic safety. Compound 11 (C₁₈) had to be excluded from the testing due to its low solubility. Compounds 9 and 10 (C₁₄, C₁₆) showed only moderate efficacy against G+ bacteria, notably with excellent potency against Staphyloccocus aureus, but no effect against G− bacteria. In contrast, non-hydroxylated isoquinolinium salts showed excellent antimicrobial efficacy within the whole series, particularly 14 (C₁₄) against G+ strains and 15 (C₁₆) against fungi. The electronic properties and desolvation energies of 5-hydroxyisoquinolinium and isoquinolinium salts were studied by quantum-chemistry calculations employing B3LYP/6-311++G(d,p) method and an implicit water-solvent simulation model (SCRF). Despite the positive mesomeric effect of the hydroxyl moiety reducing the electron density of the quaternary nitrogen, it is probably the higher lipophilicity and lower desolvation energy of isoquinolinium salts, which is responsible for enhanced antimicrobial versatility and efficacy.     

Synthesis and biological evaluation of some 17-picolyl and 17-picolinylidene androst-5-ene derivatives

Starting from dehydroepiandrosterone (1) 17-picolyl (2), 17-picolinylidene (7), 17-picolinylidene-16-one (10 and 11), and 17-picolyl-16-one (15) derivatives of androst-5-ene were synthesized in one, two, four and five steps respectively. By the Oppenauer oxidation or dehydration of 2, 7, 10, and 11 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the corresponding A and B ring modified derivatives 3, 5, 6, 8, 9, and 12-14 were obtained. The structure of 2 was unambiguously proved by the appropriate X-ray structural analysis. Compounds 3, 5, 9, 12-14 showed inhibitory activity against the enzyme aromatase. Antibacterial activity, toxicity to brine shrimp Artemia salina, antitumor activity against three tumor cell lines (human cervix carcinoma HeLa cells, human melanoma FemX cells, and human myelogenous leukemia K562 cells) and toxicity against peripheral blood mononuclear cells were evaluated. Three tested compounds, namely 11, 13, and 15, showed strong activity against all three cell lines, the IC(50) values being in the range of 4-10 microM.     

Synthesis,antimycobacterial activity and influence on mycobacterial InhA and PknB of 12-membered cyclodepsipeptides

In recent years, several small natural cyclopeptides and cyclodepsipeptides were reported to have antimycobacterial activity. Following this lead, a synthetic pathway was developed for a small series of 12-membered ring compounds with one amide and two ester bonds (cyclotridepsipeptides). Within the series, the ring system proved to be necessary for growth inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis in the low micromolar range. Open-chain precursors and analogues were inactive. The compounds modulated autophosphorylation of the mycobacterial protein kinase B (PknB). PknB inhibitors were active at µM concentration against mycobacteria while inducers were inactive. PknB regulates the activity of the mycobacterial reductase InhA, the target of isoniazid. The activity of the series against Mycobacterium bovis BCG InhA overexpressing strains was indistinguishable from that of the parental strain suggesting that they do not inhibit InhA. All substances were not cytotoxic (HeLa?>?5?µg/ml) and did not show any significant antiproliferative effect (HUVEC?>?5?µg/ml; K-562?>?5?µg/ml). Within the scope of this study, the molecular target of this new type of small cyclodepsipeptide was not identified, but the data suggest interaction with PknB or other kinases may partly cause the activity.     

Synthesis of N-substituted indole-2-carboxamides and investigation of their biochemical responses against free radicals

The antioxidant role of novel N-substituted indole-2-carboxamides (I2CDs) was investigated for their inhibitory effects on superoxide anion (O2-) and lipid peroxidation (LP). Among the synthesized I2CDs, 3, 4, 6, 8 and 9 significantly inhibited O2*- with an inhibition range at 70-98%. Examination of substituent effects on activity showed that both the ortho- and para- positions of the benzamide residue needs to be dichlorinated in order to get a maximum inhibitory effect on superoxide anion. In general, halogenated derivatives were found more active then the non-halogenated ones. However, none of the I2CDs had a significant inhibitory effects on the level of lipid peroxidation; only compounds 7 and 10 moderately decreased LP levels by over 50% at 10(-3) M concentrations.