An efficient eco-friendly, simple, and green synthesis of some new spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide derivatives as potential inhibitors of SARS-CoV-2 proteases: drug-likeness, pharmacophore, molecular docking, and DFT exploration,Molecular Diversity

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An efficient eco-friendly, simple, and green synthesis of some new spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide derivatives as potential inhibitors of SARS-CoV-2 proteases: drug-likeness, pharmacophore, molecular docking, and DFT exploration
Molecular Diversity ( IF 3.9 ) Pub Date : 2023-11-09 , DOI: 10.1007/s11030-023-10761-0
Ahmed M El-Saghier ₁ , Souhaila S Enaili _{1,

2} , Aly Abdou ₁ , Asmaa M Kadry ₁

Affiliation

Introduction

The coronavirus disease 2019 (COVID-19) pandemic has caused a global health crisis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious virus that can cause severe respiratory illness. There is no specific treatment for COVID-19, and the development of new drugs is urgently needed.

Problem statement

The SARS-CoV-2 main protease (M^pro) enzyme is a critical viral enzyme that plays a vital role in viral replication. The inhibition of M^pro enzyme can be an effective strategy for developing new COVID-19 drugs.

Methodology

An efficient operationally simple and convenient green synthesis method had been done towards a series of novel spiro-N-(4-sulfamoylphenyl)-2-carboxamide derivatives, in ethanol at room temperature in green conditions, up to 90% yield. The molecular structures of the synthesized compounds were verified using spectroscopic methods.The title compounds were subjected to in silico analysis, including Lipinski’s rule and ADMET prediction, in addition to pharmacophore modeling and molecular docking against the active site of SARS-CoV-2 target main protease (M^pro) enzyme (6LU7). Furthermore, both of the top-ranked compounds (5 and 6) and the standard Nirmatrelvir were subjected to DFT analysis.

Findings

The synthesized compounds exhibited good binding affinity to SARS-CoV-2 Mpro enzyme, with binding energy scores ranging from − 7.33 kcal/mol (compound 6) and − 7.22kcal/mol (compound 5) to − 6.54 kcal/mol (compounds 8 and 9). The top-ranked compounds (5 and 6) had lower HOMO–LUMO energy difference (ΔE) than the standard drug Nirmatrelvir. This highlights the potential and relevance of charge transfer at the molecular level.

Recommendation

These findings suggest that the synthesized spiro-N-(4-sulfamoylphenyl)-2-carboxamide derivatives could be potential candidates for COVID-19 drug development. To confirm these drugs' antiviral efficacy in vivo, more research is required. With very little possibility of failure, this proven method could aid in the search for the SARS-CoV-2 pandemic's desperately needed medications.

Graphical abstract

中文翻译：

一些新型螺-N-(4-氨磺酰基-苯基)-1,3,4-噻二唑-2-甲酰胺衍生物的高效、环保、简单和绿色合成，作为SARS-CoV-2蛋白酶的潜在抑制剂：药物-相似性、药效基团、分子对接和DFT探索

介绍

2019 年冠状病毒病 (COVID-19) 大流行已引发全球健康危机。严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是一种具有高度传染性的病毒，可引起严重的呼吸道疾病。 COVID-19尚无特效治疗方法，迫切需要开发新药。

问题陈述

SARS-CoV-2 主蛋白酶 (M ^pro ) 是一种关键的病毒酶，在病毒复制中发挥着至关重要的作用。 M^原酶的抑制可以成为开发新的COVID-19药物的有效策略。

方法

对一系列新型螺-N- (4-氨磺酰基苯基)-2-甲酰胺衍生物进行了一种高效、操作简单、方便的绿色合成方法，在乙醇中、室温、绿色条件下，收率高达90%。使用光谱方法验证了合成化合物的分子结构。对标题化合物进行了计算机分析，包括Lipinski规则和ADMET预测，以及针对SARS-CoV-2靶标主要活性位点的药效团建模和分子对接。蛋白酶 (M ^pro ) 酶 (6LU7)。此外，排名靠前的化合物（5 和 6）和标准 Nirmatrelvir 均进行了 DFT 分析。

发现

合成的化合物对 SARS-CoV-2 Mpro 酶表现出良好的结合亲和力，结合能得分范围为 - 7.33 kcal/mol（化合物6 ）和 - 7.22 kcal/mol（化合物5 ）到 - 6.54 kcal/mol（化合物8）和9 )。排名靠前的化合物（ 5和6 ）的 HOMO-LUMO 能量差 (ΔE) 低于标准药物 Nirmatrelvir。这凸显了分子水平上电荷转移的潜力和相关性。