New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents

Chiarelli, Laurent R.; Mori, Matteo; Beretta, Giangiacomo; Gelain, Arianna; Pini, Elena; Sammartino, José Camilla; Stelitano, Giovanni; Barlocco, Daniela; Costantino, Luca; Lapillo, Margherita; Poli, Giulio; Caligiuri, Isabella; Rizzolio, Flavio; Bellinzoni, M.; Tuccinardi, Tiziano; Villa, Stefania; Meneghetti, Fiorella

doi:10.1080/14756366.2019.1589462

Cited by 29 publications

(56 citation statements)

References 32 publications

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Section: Resultsmentioning

confidence: 99%

“…The new furan derivatives IV – IX were synthesized according to previously published procedures [ 13 ]. V was obtained by the same approach adopted for 1a , b , employing (3,5-bis(trifluoromethyl)phenyl)boronic acid and methyl 5-bromofuran-2-carboxylate in a traditional Suzuki–Miyaura reaction, followed by a hydrolysis of the ester function [ 13 ]. IV was obtained by reacting 3-bromo-5-(trifluoromethyl)benzonitrile with (5-(methoxycarbonyl)furan-2-yl)boronic acid in a microwave-assisted Suzuki-Miyaura coupling, followed by a base-catalyzed hydrolysis of the ester function [ 13 ].…”

Section: Resultsmentioning

confidence: 99%

“…In this context, we developed in recent years a series of furan-based carboxylic acids as MbtI inhibitors [ 12 , 13 , 14 , 15 ]. Among this class of compounds, I and II ( Figure 2 ) emerged as the best leads, exhibiting a strong MbtI inhibition, conceivably related to their antitubercular activity, and a negligible cytotoxicity towards eukaryotic cells.…”

Section: Introductionmentioning

confidence: 99%

“…On this basis, and considering our previous results on disubstituted derivatives, we decided to design and synthesize six new furan-based analogues ( IV – IX , Figure 4 ). In particular, IV was investigated as the isomer of 5-(2-cyano-4-(trifluoromethyl)phenyl)furan-2-carboxylic acid, which exhibited an interesting inhibitory effect (IC 50 of about 18 µM) [ 13 ]. The new analogue IV bears the CN and CF 3 moieties in the relative meta positions to avoid the steric interactions between the two adjacent groups, which had proven to be detrimental for the activity [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, IV was investigated as the isomer of 5-(2-cyano-4-(trifluoromethyl)phenyl)furan-2-carboxylic acid, which exhibited an interesting inhibitory effect (IC 50 of about 18 µM) [ 13 ]. The new analogue IV bears the CN and CF 3 moieties in the relative meta positions to avoid the steric interactions between the two adjacent groups, which had proven to be detrimental for the activity [ 13 ]. Compound V was synthesized to evaluate the role of the 3-CN moiety, as our past works had shown that this group was superior to other substituents in terms of enzymatic activity [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents

et al. 2021

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Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of Mycobacterium tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of I and II, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (IV–IX), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (IV), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound IV offers promising prospects for future studies on the development of novel agents against mycobacterial infections.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents

et al. 2021

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Conventional and microwave‐assisted organic synthesis of novel antimycobacterial agents bearing furan and pyridine hybrids

Desai

Bhatt

Jadeja

et al. 2021

Drug Development Research

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Drug resistance in tuberculosis poses a serious threat to humanity because currently available antitubercular drugs are ineffective against Mycobacterium tuberculosis (M. tuberculosis). As a result, the approval of Bedaquiline and Delamanid for the treatment of drug‐resistant tuberculosis was accelerated. Still, there is an urgent need to search for new antitubercular drugs with novel mechanisms of action (MoA). Due to this, we have designed a synthetic strategy by utilizing microwave‐assisted organic synthesis. We have compared our method with the conventional procedure, and the data show that our procedure is more effective in the preparation of title compounds. A unique series of 1‐(2‐(furan‐2‐yl)‐5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazol‐3(2H)‐yl)‐3‐(aryl)‐prop‐2‐en‐1‐ones (5a‐o) was synthesized utilizing conventional and microwave‐assisted techniques. Synthetic compounds were investigated for antitubercular activity against Mycobacterium TB H37Ra and Mycobacterium bovis (M. bovis). Compound 5b was reported to be the most effective against M. tuberculosis H37Ra (97.69 percent inhibition at 30 μg/ml) and M. bovis (97.09 percent inhibition at 30 μg/ml). An in silico binding affinity study of mycobacterial enoyl‐acyl carrier protein reductase (InhA) reveals the binding mechanism and thermodynamic interactions that determine these molecule's binding affinity. Compound 5b had a high glide score of −8.991 and low glide energy of −49.893 kcal/mol.

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Synthesis, characterization, and antimicrobial evaluation of some novel anthracene heterocycles derivatives

Dardeer

Taha

Elamary

2020

Journal of Heterocyclic Chem

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A series of novel heterocyclic compounds containing anthracene moiety was synthesized. Reaction of (11R,15S)‐9,10‐dihydro‐9,10‐[3,4]furanoanthracene‐12,14‐dione with 2‐cyanoacetohydrazide gave 2‐cyano‐pyrroloanthracen acetamide (1), which acts as an adaptable material for the synthesis of new heterocyclic compounds. The synthesized compounds were examined for their antimicrobial activity against Escherichia coli and Staphylococcus aureus via p‐iodonitrotetrazolium violet formazon assay. The results exhibited great activity against the tested strains with a minimum bactericidal concentration range from 0.636 to 3.8 mg/mL) and 0.159 to 3.6 mg/mL for E coli and S aureus, respectively. Interestingly, the highest activity was recorded for chromene derivative (6) against both strains.

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New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents

Cited by 29 publications

References 32 publications

Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents

Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents

Conventional and microwave‐assisted organic synthesis of novel antimycobacterial agents bearing furan and pyridine hybrids

Synthesis, characterization, and antimicrobial evaluation of some novel anthracene heterocycles derivatives

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