Amino acid derivatives. Part 6. Synthesis, in vitro antiviral activity and molecular docking study of new N-α-amino acid derivatives conjugated spacer phthalimide backbone

Al‐Masoudi, Najim A.; Abood, Einas; Al-Maliki, Ziyad T.; Al-Masoudi, Wasfi A.; Pannecouque, Christophe

doi:10.1007/s00044-016-1693-9

Cited by 13 publications

(7 citation statements)

References 44 publications

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“…Aminopyrimidines are important building blocks for the synthesis of new heterocyclic systems (Abdul-Rida et al, 2017) and they are also considered to constitute an important pharmacophoric fragment (Loving et al, 2009) because of the wide biological activities that systems containing this unit have shown, such as anti-HIV activity (Al-Masoudi et al, 2016) and cyclin-dependent kinase 2 (CDK2) inhibitory activity (Cortese et al, 2016), while aminopyrimidine-galactose hybrids have recently been developed as highly selective galectin-3 inhibitors (Dahlqvist et al, 2019). In addition, benzimidazole has been shown to be an important heterocyclic fragment present in a large number of compounds with broad biological activity, including antimicrobial and antitumour activity (El-Gohary & Shaaban, 2017).…”

Section: Introductionmentioning

confidence: 99%

A concise and efficient synthesis of amino-substituted (1H-benzo[d]imidazol-1-yl)pyrimidine hybrids: synthetic sequence and the molecular and supramolecular structures of six examples

et al. 2019

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A concise and efficient synthesis of a series of amino‐substituted benzimidazole–pyrimidine hybrids has been developed, starting from the readily available N4‐(2‐aminophenyl)‐6‐methoxy‐5‐nitrosopyrimidine‐2,4‐diamine. In each of N5‐benzyl‐6‐methoxy‐4‐(2‐phenyl‐1H‐benzo[d]imidazol‐1‐yl)pyrimidine‐2,5‐diamine, C25H22N6O, (I), 6‐methoxy‐N5‐(4‐methoxybenzyl)‐4‐[2‐(4‐methoxyphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidine‐2,5‐diamine, C27H26N6O3, (III), 6‐methoxy‐N5‐(4‐nitrobenzyl)‐4‐[2‐(4‐nitrophenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidine‐2,5‐diamine, C25H20N8O5, (IV), the molecules are linked into three‐dimensional framework structures, using different combinations of N—H…N, N—H…O, C—H…O, C—H…N and C—H…π hydrogen bonds in each case. Oxidative cleavage of 6‐methoxy‐N5‐(4‐methylbenzyl)‐4‐[2‐(4‐methylphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidine‐2,5‐diamine, (II), with diiodine gave 6‐methoxy‐4‐[2‐(4‐methylphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidine‐2,5‐diamine, which crystallized as a monohydrate, C19H18N6O·H2O, (V), and reaction of (V) with trifluoroacetic acid gave two isomeric products, namely N‐{5‐amino‐6‐methoxy‐6‐[2‐(4‐methylphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidin‐2‐yl}‐2,2,2‐trifluoroacetamide, which crystallized as an ethyl acetate monosolvate, C21H17F3N6O2·C4H8O2, (VI), and N‐{2‐amino‐6‐methoxy‐4‐[2‐(4‐methylphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidin‐5‐yl}‐2,2,2‐trifluoroacetamide, which crystallized as a methanol monosolvate, C21H17F3N6O2·CH4O, (VIIa). For each of (V), (VI) and (VIIa), the supramolecular assembly is two‐dimensional, based on different combinations of O—H…N, N—H…O, N—H…N, C—H…O and C—H…π hydrogen bonds in each case. Comparisons are made with some related structures.

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Section: Introductionmentioning

confidence: 99%

A concise and efficient synthesis of amino-substituted (1H-benzo[d]imidazol-1-yl)pyrimidine hybrids: synthetic sequence and the molecular and supramolecular structures of six examples

et al. 2019

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“…Conjugates showed moderate activity against HCV genotype 1b in the Huh-5-2 replicon system. The anti-HIV activity indicated that the synthesised conjugates act as new candidates for non-nucleoside reverse transcriptase inhibitors [ 154 ].…”

Section: Conjugated or Hybrid Moleculesmentioning

confidence: 99%

Conjugation as a Tool in Therapeutics: Role of Amino Acids/Peptides-Bioactive (Including Heterocycles) Hybrid Molecules in Treating Infectious Diseases

et al. 2023

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Peptide-based drugs are gaining significant momentum in the modern drug discovery, which is witnessed by the approval of new drugs by the FDA in recent years. On the other hand, small molecules-based drugs are an integral part of drug development since the past several decades. Peptide-containing drugs are placed between small molecules and the biologics. Both the peptides as well as the small molecules (mainly heterocycles) pose several drawbacks as therapeutics despite their success in curing many diseases. This gap may be bridged by utilising the so called ‘conjugation chemistry’, in which both the partners are linked to one another through a stable chemical bond, and the resulting conjugates are found to possess attracting benefits, thus eliminating the stigma associated with the individual partners. Over the past decades, the field of molecular hybridisation has emerged to afford us new and efficient molecular architectures that have shown high promise in medicinal chemistry. Taking advantage of this and also considering our experience in this field, we present herein a review concerning the molecules obtained by the conjugation of peptides (amino acids) to small molecules (heterocycles as well as bioactive compounds). More than 125 examples of the conjugates citing nearly 100 references published during the period 2000 to 2022 having therapeutic applications in curing infectious diseases have been covered.

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“…Besides being used to synthesize triazoles derivatives, click chemistry is also widely applied for the fusion of two or more chemical groups in a single hybrid molecule with improved biological activity (Ouyang et al, 2018 ). As triazole derivatives, the phthalimide group has been shown to be useful in the formation of hybrid compounds with antiviral activity against HIV (Al-Masoudi et al, 2016 ), cytomegalovirus and varicella-zoster (Mandić et al, 2020 ). Importantly, both triazole and phthalimide derivatives also have relevant anti-inflammatory activity (Assis et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of 1,2,3-triazole-phthalimide derivatives as potential drugs against COVID-19: a virtual screening, docking and molecular dynamic study

Holanda

Lima

Silva

et al. 2021

Journal of Biomolecular Structure and Dynamics

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In this work we aimed to perform an in silico predictive screening, docking and molecular dynamic study to identify 1,2,3-triazole-phthalimide derivatives as drug candidates against SARS-CoV-2. The in silico prediction of pharmacokinetic and toxicological properties of hundred one 1,2,3-triazole-phtalimide derivatives, obtained from SciFinderV R library, were investigated. Compounds that did not show good gastrointestinal absorption, violated the Lipinski's rules, proved to be positive for the AMES test, and showed to be hepatotoxic or immunotoxic in our ADMET analysis, were filtered out of our study. The hit compounds were further subjected to molecular docking on SARS-CoV-2 target proteins. The ADMET analysis revealed that 43 derivatives violated the Lipinski's rules and 51 other compounds showed to be positive for the toxicity test. Seven 1,2,3-triazole-phthalimide derivatives (A7, A8, B05, E35, E38, E39, and E40) were selected for molecular docking and MFCC-ab initio analysis. The results of molecular docking pointed the derivative E40 as a promising compound interacting with multiple target proteins of SARS-CoV-2. The complex E40-M pro was found to have minimum binding energy of À10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of À8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have high binding energies of À63.47 ± 3 and À63.31 ± 7 kcal/mol against SARS-CoV-2 main protease. In addition, the derivative E40 exhibited excellent interaction values and inhibitory potential against SAR-Cov-2 main protease and viral nucleocapsid proteins, suggesting this derivative as a potent antiviral for the treatment and/or prophylaxis of COVID-19.

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Amino acid derivatives. Part 6. Synthesis, in vitro antiviral activity and molecular docking study of new N-α-amino acid derivatives conjugated spacer phthalimide backbone

Cited by 13 publications

References 44 publications

A concise and efficient synthesis of amino-substituted (1H-benzo[d]imidazol-1-yl)pyrimidine hybrids: synthetic sequence and the molecular and supramolecular structures of six examples

A concise and efficient synthesis of amino-substituted (1H-benzo[d]imidazol-1-yl)pyrimidine hybrids: synthetic sequence and the molecular and supramolecular structures of six examples

Conjugation as a Tool in Therapeutics: Role of Amino Acids/Peptides-Bioactive (Including Heterocycles) Hybrid Molecules in Treating Infectious Diseases

Identification of 1,2,3-triazole-phthalimide derivatives as potential drugs against COVID-19: a virtual screening, docking and molecular dynamic study

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