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 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.     

Development of acridine derivatives as selective Mycobacterium tuberculosis DNA gyrase inhibitors

In this study we have designed p-phenylene diamine linked acridine derivative from our earlier reported quinoline–aminopiperidine hybrid MTB DNA gyrase inhibitors with aiming more potency and less cardiotoxicity. We synthesized thirty six compounds using four step synthesis from 2-chloro benzoic acid. Among them compound 4-chloro-N-(4-((2-methylacridin-9-yl)amino)phenyl)benzenesulphonamide (6) was found to be more potent with MTB DNA gyrase super coiling IC₅₀ of 5.21 ± 0.51 μM; MTB MIC of 6.59 μM and no zHERG cardiotoxicity at 30 μM and 11.78% inhibition at 50 μM against mouse macrophage cell line RAW 264.7.     

New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species

Three series of salicylanilides, esters of N-phenylsalicylamides and 2-hydroxy-N-[1-(2-hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides, in total thirty target compounds were synthesized and characterized. The compounds were evaluated against seven bacterial and three mycobacterial strains. The antimicrobial activities of some compounds were comparable or higher than the standards ampicillin, ciprofloxacin or isoniazid. Derivatives 3f demonstrated high biological activity against Staphylococcus aureus (?0.03 μmol/L), Mycobacterium marinum (?0.40 μmol/L) and Mycobacterium kansasii (1.58 μmol/L), 3g shows activity against Clostridium perfringens (?0.03 μmol/L) and Bacillus cereus (0.09 μmol/L), 3h against Pasteurella multocida (?0.03 μmol/L) and M. kansasii (?0.43 μmol/L), 3i against methicillin-resistant S. aureus and B. cereus (?0.03 μmol/L). The structure–activity relationships are discussed for all the compounds.     

Identification of Mycobacterium tuberculosis CtpF as a target for designing new antituberculous compounds

The emergence of tuberculosis (TB) produced by multi-drug resistance (MDR) and extensively-drug resistance (XDR) Mycobacterium tuberculosis (Mtb), encourages the development of new antituberculous compounds, as well as the identification of novel drug targets. In this regard, plasma membrane P-type ATPases are interesting targets because they play a crucial role in ion homeostasis and mycobacterial survival. We focused on Mtb CtpF, a calcium P-type ATPase that responds to a broad number of intraphagosomal conditions, as a novel target. In this study, we evaluated the capacity of cyclopiazonic acid (CPA), a well-known inhibitor of the sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA), to inhibit the ATPase activity of CtpF and the Mtb growth demonstrating that CtpF is a druggable target. A homology modeling of CtpF was generated for molecular docking studies of CtpF with CPA and key pharmacophoric features were identified, which were used to perform a pharmacophore-based virtual screening of the ZINC database, and to identify CtpF inhibitor candidates. Molecular docking-based virtual screening and MM-BGSA calculations of candidates allowed identifying six compounds with the best binding energies. The compounds displayed in vitro minimum inhibitory concentrations (MIC) ranging from 50 to 100 μg/mL, growth inhibitions from 29.5 to 64.0% on Mtb, and inhibitions of Ca²⁺-dependent ATPase activity in Mtb membrane vesicles (IC₅₀) ranging from 4.1 to 35.8 μM. The compound ZINC63908257 was the best candidate by displaying a MIC of 50 μg/mL and a Ca²⁺ P-type ATPase inhibition of 45% with IC₅₀ = 4.4 μM. Overall, the results indicate that CtpF is a druggable target for designing new antituberculous compounds.     

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 trehalose-based compounds and their inhibitory activities against Mycobacterium smegmatis

The synthesis of a library of trehalose-based compounds has been accomplished, and their activities against Mycobacterium smegmatis have been determined. A preliminary structure–activity relationship (SAR) is reported. Despite not having a potent lead, one of the trehalose derivatives displays strong activity when applied with isoniazid (INH), which is known to have low sterilizing activity. The bacteriocidal nature of our compounds against Mycobacterium may be significant for the development of new therapies against tuberculosis.     

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.     

Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis

Novel 3′-piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4-quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by ¹H, ¹³C and ¹⁹F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC₅₀), or inducing 25% DNA cleavage by DNA gyrase (CC₂₅). Compound 4 (with a methoxy in R₈ and a secondary carbamate in R₃′) and compound 5 (with a hydrogen in R₈ and an ethyl ester in R₃′) displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxifloxacin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R₃′ substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future.     

Design,synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis

This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125–0.250 μg/mL (0.37–0.75 μM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.     

Development of novel isatin–nicotinohydrazide hybrids with potent activity against susceptible/resistant Mycobacterium tuberculosis and bronchitis causing–bacteria

Joining the global fight against Tuberculosis, the world''s most deadly infectious disease, herein we present the design and synthesis of novel isatin-nicotinohydrazide hybrids (5a–m and 9a–c) as promising anti-tubercular and antibacterial agents. The anti-tubercular activity of the target hybrids was evaluated against drug-susceptible M. tuberculosis strain (ATCC 27294) where hybrids 5d, 5g and 5h were found to be as potent as INH with MIC = 0.24 µg/mL, also the activity was evaluated against Isoniazid/Streptomycin resistant M. tuberculosis (ATCC 35823) where compounds 5g and 5h showed excellent activity (MIC = 3.9 µg/mL). Moreover, the target hybrids were examined against six bronchitis causing-bacteria. Most derivatives exhibited excellent antibacterial activity. K. pneumonia emerged as the most sensitive strain with MIC range: 0.49–7.81 µg/mL. Furthermore, a molecular docking study has proposed DprE1 as a probable enzymatic target for herein reported isatin-nicotinohydrazide hybrids, and explored the binding interactions within the vicinity of DprE1 active site.     

Metal complexes of carboxamidrazone analogs as antitubercular agents. 1. Synthesis,X-ray crystal-structures,spectroscopic properties and antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv

N¹-Benzylidene-pyridine carboxamidrazones and their metal conjugates have emerged as a new class of potential antimycobacterial agents. Nine such carboxamidrazone analogs (L₁–L₉) along with their Cu(II) (MC₁–MC₉) and Fe(III) (MC₁₀–MC₁₈) complexes were synthesized. Single crystal X-ray structures of copper complexes MC₁ and MC₅ were determined which suggest slightly distorted square planer geometries for copper complexes and octahedral geometries for ferric compounds. All compounds were evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv. The results show 32–64-fold enhancement in antitubercular activity upon copper complexation.     

Design, synthesis and antimycobacterial activity of cinnamide derivatives: a molecular hybridization approach

A series of cinnamide derivatives was designed as potential antimycobacterial agents using molecular hybridization approach. The diamine moiety, a key feature of ethambutol and its other analogs, and certain structural features of cerulenin and cinnamic acid were hybridized to obtain cinnamide derivatives. The minimum inhibitory concentration (MIC) of all synthesized compounds was determined against M. tuberculosis H₃₇R_v using Resazurin Microtitre plate Assay (REMA) method. The synthesized molecules showed good to moderate activity with MIC in the range of 5-150 μM and good safety profile. Additionally, the most potent compound 1a, having MIC 5.1 μM exhibited synergy with rifampicin.     

Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-tubercular agents

A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular ‘click chemistry’ approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78 μg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-β-d-ribose-2′-epimerase) enzyme revealed noteworthy information on the plausible binding interactions.     

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 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 activity of 7-O-substituted-4-methyl-2H-2-chromenone derivatives vs Mycobacterium tuberculosis

A series of 7-O-alkoxy-4-methylumbelliferone derivatives were prepared using a convenient one step synthesis. Additionally the bromo- and azido derivatives 7-O-(4-bromobutoxy)-, 7-O-(6-bromohexyloxy)- and 7-O-(6-azidohexyloxy)-4-methylumbelliferone derivatives were prepared. In vitro evaluation of antimycobacterial activity determined % inhibition and MIC vs M. tuberculosis H₃₇Rv with toxicity (IC₅₀) assessed in VERO cells. The coumarins with longer alkyl chains (nonyl and decyl) showed the optimum inhibitory activity in this series (MIC 3.13?μg/mL) and IC₅₀>10?μg/mL.     

Synthesis and antimycobacterial activity of 7-O-substituted-4-methyl-2H-2-chromenone derivatives vs Mycobacterium tuberculosis

A series of 7-O-alkoxy-4-methylumbelliferone derivatives were prepared using a convenient one step synthesis. Additionally the bromo- and azido derivatives 7-O-(4-bromobutoxy)-, 7-O-(6-bromohexyloxy)- and 7-O-(6-azidohexyloxy)-4-methylumbelliferone derivatives were prepared. In vitro evaluation of antimycobacterial activity determined % inhibition and MIC vs M. tuberculosis H37Rv with toxicity (IC50) assessed in VERO cells. The coumarins with longer alkyl chains (nonyl and decyl) showed the optimum inhibitory activity in this series (MIC 3.13 microg/mL) and IC50 > 10 microg/mL.     

Design,synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis

In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H₃₇Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated for in vitro studies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H₃₇Ra, respectively.     

Activity of 7-methyljuglone derivatives against Mycobacterium tuberculosis and as subversive substrates for mycothiol disulfide reductase

The naphthoquinone 7-methyljuglone (5-hydroxy-7-methyl-1,4-naphthoquinone) has previously been isolated and identified as an active component of root extracts of Euclea natalensis which displays antitubercular activity. Herein, a series of synthetic and plant-derived naphthoquinone derivates of the 7-methyljuglone scaffold have been prepared and evaluated for antibacterial activity against Mycobacterium tuberculosis. Several of these compounds have been shown to operate as subversive substrates with mycothiol disulfide reductase. The absence of a direct correlation between antitubercular activity and subversive substrate efficiency with mycothiol disulfide reductase, might be a consequence of their non-specific reactivity with multiple biological targets (e.g. other disulfide reductases).