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\begin{document}


\def\RunningAuthor{Zambare Y. B et al.}
\firstPage{2063}
\articleType{Original Article}
\receivedDate{05 Dec 2019}
\acceptedDate{24 Dec 2019}
\revisedDate{23 Dec 2019}
\journalVolume{2020, 11}
\journalIssue{2}
\journalDoi{ijrps.v11i2.2147}
\copyrightYear{2020}
\def\authorCount{3}
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\title{Design and synthesis of novel heterocyclic compounds as a PPAR-\ensuremath{\gamma } agonist}
\author{Zambare~Y.~B\textsuperscript{*},  
            Bhole~R.~P, 
            Chitlange~S.~S~\\[5pt]{Department of Pharmaceutical Chemistry, Dr. D. Y. Patil Institute of Pharmaceutical Sciences \& Research Pimpri, Pune 411018,  Maharashtra, India}}

\begin{abstract}
The multifarious metabolic syndrome, diabetes mellitus (DM), is a diseaseof concern all over the world and is approximate to affect 400 million individuals by the 2020. Several classes of drugs at the moment are available to lessen hyperglycemia in diabetes mellitus especially in Type-II. These drugs mostly have dangerous side effects and thus incisive for a new class of compounds is necessary to conquer this inconvenience. A series of 6 novel 5-nitrobenzofuran-2yl-carbamides derivatives were synthesized and molecular docking studies were performed on PPAR-\ensuremath{\gamma } target using (PDB code-4rfm).The preparation of5-nitro-1-benzofuran-2-carbohydrazide(4)  on action with acetic acid, 1, 4-diaxone and sodium nitrite resulted  in 5-nitro-1-benzofuran-2-carbonyl azide (5).The  related compound (5) on action with substituted aromatic substituted amines undergoes Curtis type of rearrangement to give 5-nitro-\textit{N}-(sub. carbamoyl)-1-benzofuran-2-carboxamide.The characterization and identification of prepared compounds were identified on the  basis of NMR, IR, Mass and elemental analysis. Docking study of targeted compounds were done using software  Autodock Tools 1.5.6 and visualisation done by  Discovery Studio 3.5 software (Accelrys Inc. San Diego, CA USA). Molecular docking studies, the binding energies are determined to be in the range of {\textendash}5.90 to {\textendash}9.80 kcal/mol, with peroxisome proliferator activated receptor \ensuremath{\gamma } (PPAR-\ensuremath{\gamma }) receptors (PDB ID: 4RFM). The prepared  compounds have been studied for their oral glucose tolerance test to distinguish the effect on plasma glucose level. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Benzofuran,\newline 1,\newline 4 dioxane,\newline Curtis rearrangement,\newline Oral glucose Tolerance Test
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Zambare~Y.~B~\\ Phone:\ +91-9766845044~\\  Email:\ zambare007@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
        \textsc{DOI:}\ \href{https://doi.org/10.26452/\@journalDoi}{\textcolor{blue}{\underline{\smash{https://doi.org/10.26452/\@journalDoi}}}}\par%
        \vspace*{-11pt}\hrulefill\\{\fontsize{9.12}{10.12}\selectfont Production and Hosted by}\par{IJRPS |~\href{www.ijrps.com}{www.ijrps.com}}\par%
        \vspace*{-2pt}{\fontsize{9.12}{10.12}\selectfont\textcopyright\ \@copyrightYear\ $|$ All rights reserved.}\par%
        \vspace*{-11pt}\rule{\linewidth}{1.2pt}
        \makeatother
        
    
\section{Introduction}
Worldwide researchers and scientist are trying to manufacture  new drugs moieties with improved pharmacokinetic  and pharmacodynamic properties with lesser unfavourable effects. 

The available anti-diabetic agents include biguanides, sulfonylureas, glycosidase inhibitors, thiazolidinediones, and DPP-4 inhibitors. These antidiabetic agents containing drugs are commonly used to manage hyperglycemia, but have proved unsuccessful to modify the course of diabetic complications and have inadequate use because of unwanted side effects and high rates of inferior failure. The literature reviews and survey reveals that the benzofuran boast to be high-quality bioactive and perceptive molecules. Benzofuran is heterocyclic containing compounds of enormous significance in the field of pharmacy and various different fields such as cinematography, crop growing, medical sciences etc. \unskip~\citep{695154:16453167,695154:16453159}. 

Benzofuran and its similar derivatives have been suggested to possess large variety of pharmacological and biological activities such as anti-bacterial, anti-fungal, anti-diabetic, anti- inflammatory, analgesic, anti-depressant, insecticidal, central nervous system stimulants and depressant effects etc \unskip~\citep{695154:16453162,695154:16453154}. Having understood the qualities of benzofuran with the aforesaid observations and explanations, it is of interest to synthesize pharmacological and biological study and their evaluation to arrive a number of benzofuran derivatives \unskip~\citep{695154:16453157}. 

The present research plan is to amalgamate some substituted benzofuran derivates and their pharmacological and biological activities  \unskip~\citep{695154:16453160,695154:16453163}. Different substituted alcohols, other phenols and appropriate amines were treated with substituted novel benzofuran moiety to provide different derivatives \unskip~\citep{695154:16453154}. 

The final structures of the prepared compounds were identified and confirmed by Infra Red spectroscopy and 1H-Neuclear Magnetic Resonance Spectroscopy \unskip~\citep{695154:16453158}. The proposed and planned compounds were screened for anti-diabetic activity using PPAR-\ensuremath{\gamma } as at target with the standard drugs and STZ induced rat model in the well operational and developed pharmacology laboratory by using standard appropriate methods \unskip~\citep{695154:16453153,695154:16453156}. 
    
\section{Materials and Methods}
Melting point was identified by ANA Lab instrument, Thermocal and is uncorrected. Infra Red spectroscopy were recorded in KBr on instrument like SHIMADZU FT-IR version8400S and prepared compound were recorded on FT-NMR BRUCKER spectrometer version 500 MHz PMR spectra at the same frequency using DMSO and TMS used as internal standard.

\textbf{Preparation and Identification procedure of 5-Nitrosalicylaldehyde (2): }

Salicylaldehyde (25.0 gm, 0.2 mol) in 100 ml of glacial acetic acid. Added gradually 48.3 gm of calcium nitrate tetra hydrate (48.3gm, 0.2 mol) was allowed to dissolve. It was heated gradually to reflux on hot plate with continuous stirring. Heated under reflux approximately for about 3 hours. At room temperature, cooled it, poured in RBF containing 500ml ice-cold water contained in 1L beaker with continuous stirring. 

These solid precipitates were filtered under vacuum using suction pump and dried under air.  The solid was dissolved using ethyl acetate and the insoluble were filtered under vacuum. The ethyl-acetate filtrate was dried over powder of sodium sulphate and evaporated under given reduced pressure to get yellow coloured solid.  Melting point was 123-124\text{\textordmasculine}C; the yield is72.3\% \unskip~\citep{695154:16453162}. 


\bgroup
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\caption{\boldmath {Synthetic scheme of preparation of Benzofuran derivatives}}
\label{f-940d44feb4ef}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Physicochemical parameters of Benzofuranderivatives 6(a-f)} }
\label{tw-dfa61e921fa4}
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\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Compound  & \cAlignHack Molecular Formula & \cAlignHack Molecular weight & \cAlignHack Melting point (\ensuremath{^{0}}C) & \cAlignHack \% Yield & \multicolumn{3}{p{\dimexpr(.35160000000000004\linewidth-2\tabcolsep)}}{\cAlignHack CHN analysis}\\
\rowcolor{kwdboxcolor} &  & \cAlignHack  & \cAlignHack  & \cAlignHack  & \cAlignHack C \% & \cAlignHack H \% & \cAlignHack N\%\\
\tblmidrule 
\cAlignHack 6a  &
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  \cAlignHack 230-233  &
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  \cAlignHack 3.74  &
  \cAlignHack 14.16 \\
\cAlignHack 6b  &
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  \cAlignHack 312  &
  \cAlignHack 240-242  &
  \cAlignHack 71.1  &
  \cAlignHack 61.72  &
  \cAlignHack 4.25  &
  \cAlignHack 13.54 \\
\cAlignHack 6c  &
  \cAlignHack C\ensuremath{_{16}}H\ensuremath{_{13}}N\ensuremath{_{3}}O\ensuremath{_{4}} &
  \cAlignHack 312  &
  \cAlignHack 283-285  &
  \cAlignHack 74.3  &
  \cAlignHack 61.76  &
  \cAlignHack 4.18  &
  \cAlignHack 13.49 \\
\cAlignHack 6d  &
  \cAlignHack C\ensuremath{_{16}}H\ensuremath{_{13}}N\ensuremath{_{3}}O\ensuremath{_{5}} &
  \cAlignHack 327  &
  \cAlignHack 250-251  &
  \cAlignHack 68.4  &
  \cAlignHack 58.73  &
  \cAlignHack 3.98  &
  \cAlignHack 12.86 \\
\cAlignHack 6e  &
  \cAlignHack C\ensuremath{_{16}}H\ensuremath{_{13}}N\ensuremath{_{3}}O\ensuremath{_{5}} &
  \cAlignHack 327  &
  \cAlignHack 220-223  &
  \cAlignHack 69.4  &
  \cAlignHack 58.69  &
  \cAlignHack 4.03  &
  \cAlignHack 12.83 \\
\cAlignHack 6f  &
  \cAlignHack C\ensuremath{_{15}}H\ensuremath{_{10}}ClN\ensuremath{_{3}}O\ensuremath{_{4}} &
  \cAlignHack 331.5  &
  \cAlignHack 222-224  &
  \cAlignHack 78.3  &
  \cAlignHack 54.29  &
  \cAlignHack 3.06  &
  \cAlignHack 10.71 \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Spectral data of Benzofuran derivatives 6(a-f)} }
\label{tw-19ad695c9310}
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\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Compound & \cAlignHack IR bands (In cm\ensuremath{^{-1}}) & \cAlignHack Types of vibrations & \cAlignHack \ensuremath{\delta }ppm & \cAlignHack Nature of proton\\
\tblmidrule 
\cAlignHack  &
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  \cAlignHack (-NH-),({\textgreater}C=O), &
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  \cAlignHack \\
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  \cAlignHack ----  &
  \cAlignHack \\
\cAlignHack  &
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  \cAlignHack Aromatizing  &
  \cAlignHack  &
  \cAlignHack ----\\
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\cAlignHack 6b &
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\cAlignHack  &
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  \cAlignHack Aromatizing &
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  \cAlignHack 7H, Ar-H \\
\cAlignHack  &
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  \cAlignHack 3H, CH\ensuremath{_{3}}\\
\cAlignHack  &
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  \cAlignHack 9.1,  &
  \cAlignHack 1H, NH \\
\cAlignHack 6c &
  \cAlignHack 1450,  &
  \cAlignHack (-C=N-),  &
  \cAlignHack 9.0,  &
  \cAlignHack 1H, NH \\
\cAlignHack  &
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  \cAlignHack Aromatizing &
  \cAlignHack 6.9-8.7,  &
  \cAlignHack 7H, Ar-H \\
\cAlignHack  &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack 2.1 &
  \cAlignHack 3H, CH\ensuremath{_{3}}\\
\cAlignHack  &
  \cAlignHack 3410,1640,  &
  \cAlignHack (-NH-),({\textgreater}C=O), &
  \cAlignHack  &
  \\
\cAlignHack 6d &
  \cAlignHack 1470,  &
  \cAlignHack Ar-(C=C),  &
  \cAlignHack ---- &
  \cAlignHack ----\\
\cAlignHack  &
  \cAlignHack 3080 &
  \cAlignHack Aromatizing &
  \cAlignHack  &
  \cAlignHack \\
\cAlignHack  &
  \cAlignHack 3420,1620,  &
  \cAlignHack (-NH-),({\textgreater}C=O), &
  \cAlignHack  &
  \cAlignHack \\
\cAlignHack 6e &
  \cAlignHack 1530,  &
  \cAlignHack Ar-(C=C),  &
  \cAlignHack ---- &
  \cAlignHack ----\\
\cAlignHack  &
  \cAlignHack 3130 &
  \cAlignHack Aromatizing &
  \cAlignHack  &
  \cAlignHack \\
\cAlignHack  &
  \cAlignHack 3380,1720,  &
  \cAlignHack (-NH-),({\textgreater}C=O), &
  \cAlignHack  &
  \cAlignHack \\
\cAlignHack 6f &
  \cAlignHack 1430,  &
  \cAlignHack Ar-(C=C),  &
  \cAlignHack ---- &
  \cAlignHack ----\\
\cAlignHack  &
  \cAlignHack 3030 &
  \cAlignHack Aromatizing &
  \cAlignHack  &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/dedd2f46-5aa3-433c-85f6-5f5b532b0498-u1.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/dedd2f46-5aa3-433c-85f6-5f5b532b0498-u1.png}{\includegraphics{images/dedd2f46-5aa3-433c-85f6-5f5b532b0498-u1.png}}{}
\makeatother 
\caption{\boldmath {Images of the compounds (6C) in PPAR-\ensuremath{\gamma } active site}}
\label{f-70093c9802ff}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Molecular docking study of compounds (6a-6f)} }
\label{tw-5e68367a2025}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.18619999999999997\linewidth-2\tabcolsep}p{\dimexpr.22349999999999998\linewidth-2\tabcolsep}p{\dimexpr.2193\linewidth-2\tabcolsep}p{\dimexpr.2207\linewidth-2\tabcolsep}p{\dimexpr.1503\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Compound Code & \cAlignHack R-(Substituted \mbox{}\protect\newline Benzaldehyde) & \cAlignHack Binding Energy \mbox{}\protect\newline (Kcal/mol) & \cAlignHack Inhibition constant (Nm) & \cAlignHack No. of H Bonds\\
\tblmidrule 
\cAlignHack 6a  &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{5}} &
  \cAlignHack -5.90  &
  \cAlignHack 8.85  &
  \cAlignHack 2 \\
\cAlignHack 6b &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}CH\ensuremath{_{3}}(O) &
  \cAlignHack -8.20 &
  \cAlignHack 16.46 &
  \cAlignHack 2\\
\cAlignHack 6c &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}OCH\ensuremath{_{3}}(P) &
  \cAlignHack -6.90 &
  \cAlignHack 11.18 &
  \cAlignHack 1\\
\cAlignHack 6d &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}OCH\ensuremath{_{3}}(P) &
  \cAlignHack -4.50 &
  \cAlignHack 2.07 &
  \cAlignHack 2\\
\cAlignHack 6e &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}OCH\ensuremath{_{3}}(O) &
  \cAlignHack -7.28 &
  \cAlignHack 16.64 &
  \cAlignHack 2\\
\cAlignHack 6f &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}Cl &
  \cAlignHack -9.28 &
  \cAlignHack 19.64 &
  \cAlignHack 2\\
\cAlignHack Std &
  \cAlignHack Glibenclamide &
  \cAlignHack -11.25 &
  \cAlignHack 17.63 &
  \cAlignHack 2\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Antidiabetic effect by Oral Glucose Tolerance Test} }
\label{tw-c12806885b8f}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1831\linewidth-2\tabcolsep}p{\dimexpr.1669\linewidth-2\tabcolsep}p{\dimexpr.1531\linewidth-2\tabcolsep}p{\dimexpr.1773\linewidth-2\tabcolsep}p{\dimexpr.15189999999999998\linewidth-2\tabcolsep}p{\dimexpr.1677\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Group & \cAlignHack R & \cAlignHack Treatment (mg/kg) & \multicolumn{3}{p{\dimexpr(.4969\linewidth-2\tabcolsep)}}{\cAlignHack Blood Glucose Concentration (mg/dl)}\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack  & \cAlignHack  & \cAlignHack 0 min. & \cAlignHack 60 min. & \cAlignHack 120 min.\\
\tblmidrule 
\cAlignHack Normal Control \mbox{}\protect\newline (Normal Saline) &
  \cAlignHack - &
  \cAlignHack 10ml/kg &
  \cAlignHack 72.16\ensuremath{\pm}0.52 &
  \cAlignHack 95.20\ensuremath{\pm}0.70 &
  \cAlignHack 84.01\ensuremath{\pm}0.65\\
\cAlignHack 6a &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{5}} &
  \cAlignHack 200 mg/kg &
  \cAlignHack 82.10\ensuremath{\pm}0.75 &
  \cAlignHack 100.10\ensuremath{\pm}0.52 &
  \cAlignHack 92.15\ensuremath{\pm}0.50\\
\cAlignHack 6b &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}CH\ensuremath{_{3}}(O) &
  \cAlignHack 200 mg/kg &
  \cAlignHack 78.60\ensuremath{\pm}0.34 &
  \cAlignHack 96.92\ensuremath{\pm}0.46 &
  \cAlignHack 86.84\ensuremath{\pm}0.42\\
\cAlignHack 6c &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}OCH\ensuremath{_{3}}(P) &
  \cAlignHack 200 mg/kg &
  \cAlignHack 80.65\ensuremath{\pm}0.50 &
  \cAlignHack 98.33\ensuremath{\pm}0.63 &
  \cAlignHack 99.66\ensuremath{\pm}0.52\\
\cAlignHack 6d &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}OCH\ensuremath{_{3}}(P) &
  \cAlignHack 200 mg/kg &
  \cAlignHack 82.45\ensuremath{\pm}0.49 &
  \cAlignHack 92.22\ensuremath{\pm}0.70 &
  \cAlignHack 82.81\ensuremath{\pm}0.77\\
\cAlignHack 6e &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}OCH\ensuremath{_{3}}(O) &
  \cAlignHack 200 mg/kg &
  \cAlignHack 76.12\ensuremath{\pm}0.56 &
  \cAlignHack 98.86\ensuremath{\pm}0.55 &
  \cAlignHack 86.81\ensuremath{\pm}0.48\\
\cAlignHack 6f &
  \cAlignHack -C\ensuremath{_{6}}H\ensuremath{_{4}}Cl &
  \cAlignHack 200 mg/kg &
  \cAlignHack 76.86\ensuremath{\pm}0.35 &
  \cAlignHack 96.45\ensuremath{\pm}0.36 &
  \cAlignHack 86.31\ensuremath{\pm}0.32\\
\cAlignHack Standard \mbox{}\protect\newline (10 mg/kg) &
  \cAlignHack Glibenclamide &
  \cAlignHack 200 mg/kg &
  \cAlignHack 50.41\ensuremath{\pm}0.44 &
  \cAlignHack 70.55\ensuremath{\pm}0.41 &
  \cAlignHack 60.65\ensuremath{\pm}0.45\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Preparation and } \textbf{Identification procedure of ethyl 5-nitro-1-benzofuran-2-carboxylate (3):}

Mixture of 5-nitrosalicylaldehyde (2) (3.00gm,0.017mol) was dissolved in acetone (40ml), add potassium carbonate (6gm) and other reagent diethyl bromo-malonate (4.47gm,0.017mol) respectively in a 100 ml flask. Heated, reflux it on water bath, maintained the temperature up to 12 hours. The completion of the reaction was observed by using TLC. When the reaction was complete, cooled at room temperature, mixture is filtered by vacuum under suction, potassium salts were washed with dry ether as a solvent. 

The dry compounds salt was added in water and cooled thoroughly by ice-cold water. The suspension of compounds was carefully acidified with dilute hydrochloric acid and the Ethyl 5-nitrobenzofuran-2-carboxylate solids were collected and separated by filtration. Methanol used for recystallizing the product and to acquire pure compound 3, as yellow crystal. Melting point of prepared compounds were observed between 145-147\text{\textordmasculine}C; the yield is 52\% \unskip~\citep{695154:16453154,695154:16453158}.

\textbf{Synthesis of 5-Nitrobenzofuran-2-carbohydrazide (4):}

Ethyl 5-nitrobenzofuran-2-carboxylate (3) (1.0gm, 0.004 mole) was dissolved in 5-ml methanol, added Hydrazine hydrate (0.25gm,0.004mol). Heated to reflux and maintained for 2 hours. The solid product was insoluble in methanol starts precipitating. The completed reaction was examined by TLC. The solvent was allowed to evaporate to get a solid product, water was added to remove excess hydrazine hydrate and extracted using ethyl acetate. Layer of Ethyl acetate was washed using water and dried over sodium sulphate powder and evaporated to get solid final compound. Melting point is 252-2540C; the yield is 60.63\% \unskip~\citep{695154:16453154,695154:16453158}.

\textbf{Synthesis of 5-Nitrobenzofuran-2-carboxyazide(5)}:

5-Nitrobenzofuran-2-carboxyhydrazide (4) (5.0gm,0.02mole)was dissolved in a equimolar mixture of (30ml) of pure glacial acetic acid and (30ml)of1,4-dioxane and cooled at 0\ensuremath{^{0}}C using ice bath containing salt. An ice-cold sodium nitrite solution (1.6 gm, 0.02 mole) in water (10 ml) was added in small portions while stirring vigorously, the temperature of the mixture was maintained below 2\text{\textordmasculine}C. When the addition was completed, reacted mixture was allowed to stand at room temperature for about 30 min and then cream colour solid that precipitatesd was collected, washed few times in cold water. In desiccators, solid compounds were dried and immediately used in next step reaction. Melting point is 95-97\text{\textordmasculine}C; the yield is 57.25\% \unskip~\citep{695154:16453162,695154:16453154}.

\textbf{General }\textbf{procedure And identification }\textbf{for the preparation}\textbf{\space }\textbf{of }\textbf{aryl-5- }\textbf{nitro benzofuran -2- carbamides. } \textbf{6(a-f)}:

A mixture of 5- Nitrobenzofuran-2-carboxyazide (5) (0.3 gm, 0.0013 mole), suitable substituted amine (0.0013 mole) and anhydrous toluene (15 ml) were heated and reflux at 120\text{\textordmasculine}C by using oil bath for 4 hours. Completed reaction was observed under TLC. Recrysatllised from ethanol. Report final yield \unskip~\citep{695154:16453162,695154:16453154}. The systematic scheme for the preparation of benzofuran mentioned in (Figure~\ref{f-940d44feb4ef}). Physicochemical and analytical data of the synthesized compound thus prepared and depicted in (Table~\ref{tw-dfa61e921fa4}) and (Table~\ref{tw-19ad695c9310}).

\textbf{Molecular Docking study}

Docking study of targeted compounds were done using software Autodock Tools 1.5.6 and visualisation done by Discovery Studio 3.5 software (Accelrys Inc. San Diego, CA USA) depicted in (Figure~\ref{f-70093c9802ff}),\unskip~\citep{695154:16453151,695154:16453161}. All dock score were performed to inspect the complete intermolecular interaction between the ligand-target proteins \unskip~\citep{695154:16453155,695154:16453152}. The observed binding energies takes place between ligand and receptors were recorded in (Table~\ref{tw-5e68367a2025}).

\textbf{Oral glucose tolerance test}

All the prepared compounds were first of all evaluated for the stage of oral glucose tolerance test (OGTT) to distinguish the effect on plasma glucose level \unskip~\citep{695154:16453164}. The compounds efficacies 6a-6f were compared by standard drug glibenclamide \unskip~\citep{695154:16453165,695154:16453166}. The results and analysis of the compounds showed that all the six compounds (6a, 6b, 6c, 6d, 6e and 6f) does not show significant antidiabetic compared to standard drugs. The results are mentioned in (Table~\ref{tw-c12806885b8f}).
    
\section{Results and Discussion}
A new series of 5-nitrobenzofuran carbamides derivatives is prepared and characterized, analysed by spectroscopic techniques Infrared, 1H NMR, and LC Mass spectra. All the compounds 6a-6f do not show the significant activity as compared to standard glibenclamide. According to molecular docking studies, the binding energies are determined to be in the range of {\textendash}5.90 to {\textendash}9.80 kcal/mol, with peroxisome proliferator activated receptor \ensuremath{\gamma } (PPAR-\ensuremath{\gamma }) receptors (PDB ID: 4RFM). All the compound do not exhibits the binding affinity. The accumulated data can be helpful in designing and optimizing the studied hybrid molecules as new oral antidiabetic agents.
    
\section{Conclusion }
As we have prepared the 5-nitrobenzofuran carbamides derivatives but the entire compound does not produce any significant activity for the antidiabetic study. So present derivatives not being suitable for the antidiabetic activity.
\section*{Acknowledgement}The authors are thankful to Dr. Agasimundin, Y. S. for giving the guidance to transmit out the research work.
    

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