Review

. 2020 Nov 4;25(21):5133.

doi: 10.3390/molecules25215133.

An Updated Review on the Synthesis and Antibacterial Activity of Molecular Hybrids and Conjugates Bearing Imidazole Moiety

Renzo Rossi¹, Maurizio Ciofalo²

Affiliations

¹ Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via G. Moruzzi, 3, I-56124 Pisa, Italy.
² Dipartimento di Scienze Agrarie, Alimentari e Forestali, University of Palermo, Viale delle Scienze, Edificio 4, I-90128 Palermo, Italy.

PMID: 33158247
PMCID: PMC7663458
DOI: 10.3390/molecules25215133

Review

An Updated Review on the Synthesis and Antibacterial Activity of Molecular Hybrids and Conjugates Bearing Imidazole Moiety

Renzo Rossi et al. Molecules. 2020.

. 2020 Nov 4;25(21):5133.

doi: 10.3390/molecules25215133.

Authors

Renzo Rossi¹, Maurizio Ciofalo²

Affiliations

¹ Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via G. Moruzzi, 3, I-56124 Pisa, Italy.
² Dipartimento di Scienze Agrarie, Alimentari e Forestali, University of Palermo, Viale delle Scienze, Edificio 4, I-90128 Palermo, Italy.

PMID: 33158247
PMCID: PMC7663458
DOI: 10.3390/molecules25215133

Abstract

The rapid growth of serious infections caused by antibiotic resistant bacteria, especially the nosocomial ESKAPE pathogens, has been acknowledged by Governments and scientists and is one of the world's major health problems. Various strategies have been and are currently investigated and developed to reduce and/or delay the bacterial resistance. One of these strategies regards the design and development of antimicrobial hybrids and conjugates. This unprecedented critical review, in which our continuing interest in the synthesis and evaluation of the bioactivity of imidazole derivatives is testified, aims to summarise and comment on the results obtained from the end of the 1900s until February 2020 in studies conducted by numerous international research groups on the synthesis and evaluation of the antibacterial properties of imidazole-based molecular hybrids and conjugates in which the pharmacophoric constituents of these compounds are directly covalently linked or connected through a linker or spacer. In this review, significant attention was paid to summarise the strategies used to overcome the antibiotic resistance of pathogens whose infections are difficult to treat with conventional antibiotics. However, it does not include literature data on the synthesis and evaluation of the bioactivity of hybrids and conjugates in which an imidazole moiety is fused with a carbo- or heterocyclic subunit.

Keywords: antibacterials; antibiotic resistance; antibiotics; bioactivity; imidazoles; molecular conjugates; molecular hybrids; synthesis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Structure of metronidazole.

**Scheme 1**
Synthesis of 5-nitroimidazole/pyrrole hybrids 2a–f.

**Figure 2**
Structure of (Z)-2-[(5-nitrofuran-2-yl)methylene]benzofuran-3(2H)-ones 7.

**Scheme 2**
Synthesis of hybrids 8 and 9.

**Figure 3**
Structures and yields of some representative compounds 8 and 9 synthesised according to Scheme 2.

**Scheme 3**
Synthesis of 3(2H)-benzofuranones **11.**

**Scheme 4**
Synthesis of 4-[5-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,3,4-thiadiazol-2-yl] thiomorpholine-1,1-dioxide (**16a**).

**Figure 4**
Structure of 4-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]thiomorpholine-1,1-dioxide (**16b**).

**Scheme 5**
Synthesis of hybrids 21–30 starting from metronidazole (1).

**Scheme 6**
Synthesis of metronidazole/1,2,3-triazole conjugates **38.**

**Scheme 7**
Synthesis of 5-nitroimidazole/3-sulfanyl-1,2,4-triazole hybrids **41a**–e and 5-nitroimidazole/1,2,4-triazole-3-thione hybrids **44a**–e.

**Scheme 8**
Synthesis of (S)-N-{[3-(3-fluoro-4-{4-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]-piperazin-1-yl}phenyl)-2-oxooxazolidin-5-yl]methyl}acetamide (45).

**Scheme 9**
Synthesis of (S)-N-({3-[3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxooxazolidin-5-yl} methyl)acetamide hydrochloride (S)-(46).

**Scheme 10**
Synthesis of (S)-N-{[3-[3-fluoro-4-[4-[5-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,3,4-thiadiazol-2-yl]-1-piperazinyl]phenyl-2-oxooxazolidin-5-yl]methyl}acetamide (S)-(48) from (S)-46 and chlorothiadiazole **19.**

**Scheme 11**
Synthesis of 2-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfonyl]-1,3,4-thiadiazoles **56a**–c.

**Scheme 12**
Synthesis of 5-nitroimidazole/1,3,4-oxadiazole hybrids **62a**–i and **63a**–i.

**Figure 5**
Structures of berberine (70) and hybrids **71.**

**Scheme 13**
Synthesis of nitroimidazole/berberine hybrids **71a**–k.

**Scheme 14**
Synthesis of hybrid **78.**

**Scheme 15**
Synthesis of methyl (1R,4aS)-7-isopropyl-1,4a-dimethyl-9-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]-2,3,4,4a,9,13c-hexahydro-1H-dibenzo[a,c]carbazole-1-carboxylate (82).

**Scheme 16**
Synthesis of hybrids **87a**–j.

**Scheme 17**
Synthesis of metronidazole/triazole conjugates 89 and 1-(prop-2-yn-1-yl)-1H-pyrazole (**90g**).

**Scheme 18**
Synthesis of quinolone/imidazole hybrids **93a**–l.

**Figure 6**
Structure of hybrid **93i.**

**Scheme 19**
Synthesis of N-substituted metronidazole/tetramic acid hybrids **98.**

**Scheme 20**
Synthesis of L-aminoacid-linked porphyrin-nitroimidazole adducts DPIX-Lys(Boc)-Nim adducts **107a** and **107b.**

**Scheme 21**
Synthesis of naphthalimide-derived metronidazoles **112a**–g.

**Scheme 22**
Synthesis of (E)-3-[(1-methyl-5-nitro-1H-imidazol-2-yl)methylene]indolin-2-one (**121**) and (E)-3-[(1-methyl-5-nitro-1H-imidazol-2-yl)methylene]-5-nitroindolin-2-one (**123**).

**Scheme 23**
Synthesis of berberine/nitroimidazole hybrids **125.**

**Scheme 24**
Synthesis of nitroimidazole/7-chloroquinoline conjugates **131a**–d.

**Scheme 25**
Synthesis of naphthalimide/nitroimidazole hybrids **137a**–d and **138a**–j.

**Scheme 26**
Synthesis of enone bridged indole/nitroimidazole conjugates **141a**–c, **142a**–i, and **143a**–f.

**Scheme 27**
Synthesis of double nitroimidazole **150.**

**Scheme 28**
Synthesis of hybrids **154a**–e.

**Scheme 29**
Synthesis of hybrids **158a**–e.

**Scheme 30**
Synthesis of conjugates **160a**–g and **163a**–f.

**Figure 7**
Structure of sodium (Z)-4-(2-hydroxyphenyl)-4-(4,5-diphenyl-1H-imidazol-2-yl)but-3-enoates **164a**–f.

**Scheme 31**
Synthesis of coumarin derivatives **165** containing imidazole skeleton.

**Scheme 32**
Synthesis of coumarin/imidazole conjugates **170.**

**Scheme 33**
Synthesis of coumarin/imidazole conjugates **171** and **172.**

**Scheme 34**
Synthesis of methylimidazolium/furanchalcone hybrids **175.**

**Scheme 35**
Synthesis of 3-{1-(benzofuran-2-yl)-2-[(2-methyl-4-oxoquinazolin-3(4H)-yl)amino] ethyl}-1-methyl-1H-imidazol-3-ium chlorides **181a**–i.

**Scheme 36**
Synthesis of compounds **183a**–c and **182a**–c.

**Scheme 37**
Synthesis of imidazole substituted 6-methylidene-penems **194a**–e and **191a**–e.

**Figure 8**
Structures of imidazole containing bisazetidinones **195** and **196.**

**Scheme 38**
Synthesis of compounds **195a**–j.

**Scheme 39**
Synthesis of compounds **196a**–j.

**Scheme 40**
Synthesis of compounds **207a**–e.

**Figure 9**
Structures of nagelamide J (**212**) and sceptrin (**213**).

**Scheme 41**
Total synthesis of *ent*-sceptrin (*ent*-**213**).

**Figure 10**
Structure of clathridimine (**228**).

**Scheme 42**
Synthesis of 1-[1-(1-aryl-4,5-diphenyl-1H-imidazol-2-yl)-2-methyl-5-phenyl-1H-pyrrol-3-yl]ethan-1-ones **229a**–l.

**Scheme 43**
Synthesis of 1-substituted 3-(4,5-diaryl-1H-imidazol-2-yl)-2-(1H-imidazol-1-yl)-1H-indoles **233a**–l.

**Scheme 44**
Synthesis of imidazole/indole hybrids **236** and **237.**

**Scheme 45**
Synthesis of oroidin (**245a**) from (E)-4-(3-aminoprop-1-en-1-yl)imidazole)-2-amine (**246**) and 4,5-dibromo-1H-pyrrole-2-carboxylic acid (**247a**).

**Figure 11**
Structures of clathrodin (**245b**) and 1H-pyrrole-2-carboxylic acid (**247b**).

**Scheme 46**
Synthesis of 1,5-disubstituted 4-[(1H-imidazol-1-yl)(phenyl)methyl]-1H-pyrazoles **248e**–o.

**Scheme 47**
Synthesis of 1,5-disubstituted 4-[(1H-imidazol-1-yl)(phenyl)methyl]-1H-pyrazoles **248p**–u.

**Scheme 48**
Synthesis of 4-(1H-imidazol-1-yl)-3,5-diaryl-4,5-dihydro-1H-pyrazole derivatives **258a**–t.

**Scheme 49**
Synthesis of 3-aryl-4-(4,5-diaryl-1H-imidazol-2-yl)-1H-pyrazoles **264a**–j.

**Scheme 50**
Synthesis of hybrids **265a**–d.

**Scheme 51**
Synthesis of N-(4-aryl-1H-imidazol-2-yl)-4-phenyl-1H-pyrazole-3-carboxamides **270a**–c.

**Scheme 52**
Synthesis of 4-(2-aryl-4,5-diphenyl-1H-imidazol-1-yl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-ones **275.**

**Scheme 53**
Synthesis of 3-(2-aryl-4,5-diphenyl-1H-imidazol-1-yl)-1H-1,2,4-triazole-5-carboxylic acid derivatives **277.**

**Scheme 54**
Synthesis of imidazole/1,2,3-triazole hybrids **279.**

**Scheme 55**
Synthesis of imidazole/1,2,3-triazole hybrids **280.**

**Scheme 56**
Synthesis of 2,4,5-trisubstituted 1H-imidazole/1,2,3-triazole hybrids **287.**

**Scheme 57**
Synthesis of 1,2,3-triazole substituted naphthaldehydes **288.**

**Scheme 58**
Synthesis of isoxazolidine/imidazole hybrids **291a**–j.

**Scheme 59**
Synthesis of 1,3,4-oxadiazole/imidazole hybrids **297a**–l.

**Scheme 60**
Synthesis of 2-aryl-5-[(2-methyl-4-nitro-1H-imidazol-1-yl)methyl]-1,3,4-oxadiazoles **300a**–l.

**Scheme 61**
Synthesis of 1,8-naphthalimide-derived imidazoles **302a**–d and **303a**–d.

**Scheme 62**
Synthesis of Schiff base-linked imidazolyl naphthalimides **306**, **307a**–c, **308a**–e, and **309a**–k.

**Scheme 63**
Synthesis of 1-aryl-3-(1H-imidazol-1-yl)-2-[(1H-imidazol-1-yl)methyl]propan-1-ones **315a**–h, 1-aryl-3-(1H-imidazol-1-yl)-2-[(1H-imidazol-1-yl)methyl]propan-1-ols **316b**,f, and 1-(5-substituted-thiophen-2-yl)-3-(1H-imidazol-1-yl)-2-[(1H-imidazol-1-yl)methyl]propan-1-ones **317a**–c.

**Scheme 64**
Synthesis of amine-derived bis-imidazoles **323a**–i and hydrochlorides **324a**–d.

**Scheme 65**
Synthesis of bis-imidazole sulfonamides **326a**–c.

**Scheme 66**
Synthesis of imidazolium geminal dicationic ionic liquids **329a**–f and **330d**–f.

**Scheme 67**
Synthesis of bis(imidazole)-pyridines **331a**–g.

**Figure 12**
Structures of imidazole-pyridine fluorophores 2PBI (**336**), 3PBI (**337**), TPBI (**338**), and MPBI (**339**).

**Scheme 68**
Synthesis of hybrids 2PBI (**336**) and 3PBI (**337**).

**Scheme 69**
Synthesis of imidazole-pyridine fluorophores TPBI (**338**) and MPBI (**339**).

**Scheme 70**
Synthesis of compounds **350a**–e.

**Scheme 71**
Synthesis of compounds **351a**–e.

**Scheme 72**
Synthesis of bipyridine derivatives **352**, **353**, and **354.**

**Scheme 73**
Synthesis of 2-(2-aryl-4,5-diphenyl-1H-imidazol-1-yl)-6-methylpyridines **360a**–d.

**Scheme 74**
Synthesis of 2-chloro-7-methylquinoline-3-carbaldehyde-based imidazole derivatives, **362a**–h.

**Scheme 75**
Synthesis of (Z)-N-{4-[(2-chloroquinolin-3-yl)methylene]-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl}arenamides **367a**–l.

**Scheme 76**
Synthesis of 4-quinolone/imidazole hybrids **371** and **372**.

**Scheme 77**
Synthesis of hybrids **379a**–j.

**Scheme 78**
Synthesis of hybrids **380a**–e.

**Scheme 79**
Synthesis of quinoline/imidazole hybrids **383a**–h, **384a**–h, **385a**–h, and **386a**–h.

**Scheme 80**
Synthesis of hybrids **393a**–f.

**Scheme 81**
Synthesis of quinoline-based hydroxyimidazolium hybrids **398a**–h.

**Scheme 82**
Synthesis of imidazolyl pyrimidines **403a**–g.

**Scheme 83**
Synthesis of hybrids **405.**

**Scheme 84**
Synthesis of imidazole-based heterocycles **412** and **413.**

**Figure 13**
Structure of onychine (**414**).

**Scheme 85**
Synthesis of 2-aryl-4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-5H-indeno [1,2-b]pyridin-5-ones **415.**

**Scheme 86**
Synthesis of imidazole appended cholestane based-conjugates **419a**–c and **420a**–c.

**Scheme 87**
Synthesis of C-12-substituted berberine/imidazole hybrids **423a**–j.

**Scheme 88**
Synthesis of N-(4-aryilidene-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl)-5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carboxamides **425a**–g.

**Scheme 89**
Synthesis of 3-(4,5-diphenyl-1H-imidazol-2-yl)-4H-chromen-4-ones **428** and 3-(1-allyl-4,5-diphenyl-1H-imidazol-2-yl)-4H-chromen-4-ones **431.**

**Figure 14**
Structure of morinidazole (**432**).

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An Updated Review on the Synthesis and Antibacterial Activity of Molecular Hybrids and Conjugates Bearing Imidazole Moiety

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An Updated Review on the Synthesis and Antibacterial Activity of Molecular Hybrids and Conjugates Bearing Imidazole Moiety

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