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Design, Synthesis, Molecular Modeling Study and Biological Evaluation of New N'-Arylidene-pyrido [2,3-d]pyrimidine-5-carbohydrazide Derivatives as Anti-HIV-1 Agents.

ABSTRACT: In an attempt to identify potential new agents that are active against HIV-1, a series of novel pyridopyrimidine-5-carbohydrazide derivatives featuring a substituted benzylidene fragment were designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors. The cytotoxicity profiles of these compounds showed no significant toxicity to human cells and they exhibited anti-HIV-1 activity with EC50 values ranging from 90 to 155 µM. Compound 5j bearing 4-methylbenzylidene group was found to be the most active compound with EC50 = 90 µM and selectivity index, CC50/EC50 = 6.4. Molecular modeling studies indicated the capacity of compound 5j to interact with two Mg2+ cations and several residues that are important in HIV-1 integrase inhibition. These findings suggested that pyridopyrimidine-5-carbohydrazide scaffold might become a promising template for development of novel anti-HIV-1 agents.

SUBMITTER: Ebrahimzadeh E

PROVIDER: S-EPMC7393058 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Design, Synthesis, Molecular Modeling Study and Biological Evaluation of New N'-Arylidene-pyrido [2,3-<i>d</i>]pyrimidine-5-carbohydrazide Derivatives as Anti-HIV-1 Agents.

Ebrahimzadeh Elnaz E Tabatabai Seyyed Abbas SA Vahabpour Rouhollah R Hajimahdi Zahra Z Zarghi Afshin A

Iranian journal of pharmaceutical research : IJPR 20190101 Suppl1

In an attempt to identify potential new agents that are active against HIV-1, a series of novel pyridopyrimidine-5-carbohydrazide derivatives featuring a substituted benzylidene fragment were designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors. The cytotoxicity profiles of these compounds showed no significant toxicity to human cells and they exhibited anti-HIV-1 activity with EC50 values ranging from 90 to 155 µM. Compound 5j bearing 4-methylbenzylidene gro ...[more]

PMID: 32802103

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Project description:BackgroundDespite significant progresses in antimicrobial therapy, infectious diseases caused by bacteria and fungi remain a major worldwide health problem because of the rapid development of resistance to existing antimicrobial drugs. Therefore, there is a constant need for new antimicrobial agents. There are a large number of heterocyclic derivatives containing nitrogen atoms that possess a broad spectrum of biological activities including pyridine and pyridazine, which are two of the most important heterocycles in medicinal chemistry.ResultsThe reaction of 3-oxo-2-arylhydrazonopropanals 2 with ethyl cyanoacetate and malononitrile 3a,b has led to the formation of 2-amino-5-arylazo-6-aryl substituted nicotinates 8a-k as sole isolable products when the aryl group in the arylazo moiety was substituted with an electron-withdrawing group like Cl, Br, NO2. The pyridazinones 10 were formed from the same reaction when the arylazo moiety was phenyl or phenyl substituted with an electron-donating group. The 2-aminoazonicotinates 8 were condensed with DMF-DMA to afford the amidines 13a,b, which then were cyclized to afford the targeted pyrido[2,3-d]pyrimidine derivatives 15a,b, respectively. The structures of all new substances prepared in this investigation were determined by using X-ray crystallographic analysis and spectroscopic methods. Most of the synthesized compounds were tested and evaluated as antimicrobial agents and the results indicated that many of the obtained compounds exhibited high antimicrobial activity comparable to ampicillin, which was used as the reference compound.ConclusionA general rule for the synthesis of 2-amino-5-arylazo-6-aryl substituted nicotinic acid and pyridazinone was established using 3-oxo-2-arylhydrazonopropanal as a precursor. Moreover, a novel route to pyrido[2,3-d]pyrimidine was achieved. Most of the synthesized compounds were found to exhibit strong inhibitory effects on the growth of Gram-positive bacteria especially Bacillus subtilis. Compounds 1a, 8a-h, 10a-c, 15b and 16 showed a broad spectrum of antimicrobial activity against B. subtilis.

Dataset Information

Design, Synthesis, Molecular Modeling Study and Biological Evaluation of New N'-Arylidene-pyrido [2,3-d]pyrimidine-5-carbohydrazide Derivatives as Anti-HIV-1 Agents.

Publications

Design, Synthesis, Molecular Modeling Study and Biological Evaluation of New N'-Arylidene-pyrido [2,3-<i>d</i>]pyrimidine-5-carbohydrazide Derivatives as Anti-HIV-1 Agents.

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