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\begin{document}


\def\RunningAuthor{Suhail H. Derawey et al.}
\firstPage{2342}
\articleType{Original Article}
\receivedDate{04.04.2019}
\acceptedDate{17.07.2019}
\revisedDate{12.07.2019}
\journalVolume{10}
\journalIssue{3}
\journalDoi{ijrps.v10i3.1477}
\copyrightYear{2019}
\def\authorCount{4}
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\title{Synthesis, characterization and antibacterial\textbf{\space }evaluation of 1,3,4-oxadiazole derivatives\textbf{\space }}
\author{Suhail~H.~Derawey\textsuperscript{*}\textsuperscript{1},  
            Mazin~N.~Mosa\textsuperscript{1},  
            Ekhlas~Qanber~Jasim\textsuperscript{1}, 
            Rawaa~M.~O.~Hraishawi\textsuperscript{2}~\\[5pt]{\textsuperscript{1}Department of pharmaceutical chemistry\unskip, College of pharmacy, University of Basrah, Iraq}~\\{\textsuperscript{2}Department of clinical laboratory sciences\unskip, College of Pharmacy, University of Basrah, Iraq}}

\begin{abstract}
The present work includes synthesis and characterization of some novel 1,3,4-oxadiazole derivatives and the evaluation of the antibacterial activity of the synthesized compound against pathogenic isolated gram-negative and gram-positive bacteria. The activity result showed that some compound exhibited efficient effect against these bacteria. Some compounds had significant inhibition zone against Escherichia coli, pseudomonas aeruginosa and Staphylococcus aureus. The compound OXD3 and OXD4 gave inhibition zone against resistant pseudomonas aeruginosa while stander drug cefepime doesn't give an activity.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}heterocyclic compound,\newline antibacterial,\newline Oxadiazole -3- thiol deravitive
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Suhail~H.~Derawey~\\ Phone:\ +9647707310975~\\  Email:\ s.hussein975@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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        \makeatother
        
    
\section{Introduction}
The compound 1,3,4-Oxadiazole is a heterocyclic compound comprising two   nitrogen atoms and an oxygen atom in a pentagonal ring. Two pyridine type nitrogen replaces two methylene groups in furan to result in the oxadiazole. Three isomers are available for oxadiazole. These are 1,3,4-oxadiazole, 1,2,3-oxadiazole, and 1,2,4-oxadiazole. Two of these are more interesting to the researchers due to their known attention-grabbing biological and chemical properties. These two are 1,3,4-oxadiazole and 1,2,4-oxadiazole \unskip~\citep{582641:13494087,582641:13494088,582641:13494089,582641:13494090}. 1,3,4-oxadiazole is a pentagonal hetrocyclic ring which is thermally stable having a boiling point at 150 \ensuremath{^{o}}C and is liquid at room temperature.

1,3,4-Oxadiazole is a useful main molecule for designing possible bioactive agents. The derivatives of this compound can exhibit different biological properties like antimicrobial, antimalarial, anti-HIV, antitubercular, anti-inflammatory, analgesic, anticonvulsant, hypoglycemic and additional biological activities such as lipid peroxidation inhibitor \unskip~\citep{582641:13494091,582641:13494092}.

Some compounds have been studied for their biological activity against \textit{C.albicans } and\textit{ S.aureus }and for other two fungi. These compounds are 3  -Aetyl-5-(4-flourophenyl)-2-substituted-2,3-dihydro-1,3,4-oxadiazoles and 5-(naphthyloxymethyl)-1,3,4-oxadiazole-2(3\textit{H})-one. The screened compounds exhibited moderate activity \unskip~\citep{582641:13494093,582641:13494094,582641:13494095}. 

Many methods can be used to prepare 2,5-Disubstituted 1,3,4-oxadiazoles, hydrazine and carboxylic acids can be used as the starting compounds; they are altered into diacylhydrazides via many precursors to result in 1,3,4-oxadiazole.; these compounds could also be synthesized by cyclodehydration of diacylhydrazines and diaroylhydrazines under the effect of different dehydrating agents (PCl\ensuremath{_{5}}, organic acid anhydrides, and H\ensuremath{_{2}}SO\ensuremath{_{4}}). The aim of the study includes the synthesis of six 1,3,4-oxadiazole compounds starting from valeric acid \unskip~\citep{582641:13494096,582641:13494097}. The synthesized compounds were characterized using different spectroscopic analysis. The antibacterial activity was evaluated for these compounds against some microorganism strains. The results showed that some compounds gave significant activity \unskip~\citep{582641:13494098}.

\textbf{Aim of the study}

Synthesis of new compounds with antibacterial activity and to promote the elimination of antibiotic-resistant bacteria.\textbf{\space }
    
\section{Materials and Methods}
\textbf{Experimental }

 All solvents and reagents were of analytical grade unless indicated otherwise and all experiments were performed with deionized water (\ensuremath{\Omega }-cm 18.2) resistivity at 25 \ensuremath{^{o}}C \unskip~\citep{582641:13494099}.


\begin{table*}[!htbp]
\caption{\boldmath {Synthesized Oxadiazole compounds} }
\label{tw-ea21308882d0}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.5168\linewidth-2\tabcolsep}p{\dimexpr.25199999999999996\linewidth-2\tabcolsep}p{\dimexpr.14489999999999995\linewidth-2\tabcolsep}p{\dimexpr.08629999999999999\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Name of compounds  & R & Symbol  & No. \\
\tblmidrule 
5  -butyl-1,3,4-oxadiazole-2-thiol  &
  -H  &
  OXD  &
    1 \\
2  -butyl-5-(ethylthio)-1,3,4-oxadiazole  &
  -CH\ensuremath{_{2}}CH\ensuremath{_{3}} &
  OXD1  &
    2 \\
2  -butyl-5-(butylthio)-1,3,4-oxadiazole  &
  -(CH\ensuremath{_{2}})3CH\ensuremath{_{3}} &
  OXD2  &
    3 \\
2  -butyl-5-(pentylthio)-1,3,4-oxadiazole  &
  -(CH\ensuremath{_{2}})4CH\ensuremath{_{3}} &
  OXD3  &
    4 \\
2  -benzyl-5-butyl-1,3,4-oxadiazole  &
  -(CH\ensuremath{_{2}})C\ensuremath{_{6}}H\ensuremath{_{5}} &
  OXD4  &
  5\\
2  - ((5-butyl-1,3,4-oxadiazol-2-yl)thio)acetic acid &
  -CH\ensuremath{_{2}}COOH  &
  OXD5  &
    6 \\
ethyl 2-(5-butyl-1,3,4-oxadiazol-2-yl)acetat  &
  -CH\ensuremath{_{2}}COOCH\ensuremath{_{2}}CH\ensuremath{_{3}} &
  OXD6  &
    7 \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Physical properties of products} }
\label{tw-7f6e25aedf3c}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1232\linewidth-2\tabcolsep}p{\dimexpr.11899999999999999\linewidth-2\tabcolsep}p{\dimexpr.13620000000000001\linewidth-2\tabcolsep}p{\dimexpr.2231\linewidth-2\tabcolsep}p{\dimexpr.1102\linewidth-2\tabcolsep}p{\dimexpr.12610000000000001\linewidth-2\tabcolsep}p{\dimexpr.16219999999999995\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Compound & M. Wt.  \mbox{}\protect\newline (gm/mole)  & p.b  \mbox{}\protect\newline (oC)  & Appearance  & Yield (\%)  & Rf  & Eluent \\
\tblmidrule 
OXD &
  158.05 &
  155-157 &
  Yellowish oily liquid &
  72.8 &
  0.78 &
  \multicolumn{1}{p{\dimexpr(.16219999999999995\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Ethyl acetate: ethanol (7:3)}}\\
OXD1 &
  186.27 &
  174-176 &
  Pale yellowish oily liquid &
  69.28 &
  0.70 &
  \\
OXD2 &
  182.14 &
  184-187 &
  Yellowish oily liquid &
  86.11 &
  0.82 &
  \multicolumn{1}{p{\dimexpr(.16219999999999995\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Ethyl acetate: ethanol (9:1)}}\\
OXD3 &
  192.16 &
  192-194 &
  Pale yellowish oily liquid &
  85.93 &
  0.72 &
  \\
OXD4 &
  213.16 &
  230-232 &
  Dark yellowish liquid &
  74.3 &
  0.86 &
  Ethyl acetate: ethanol (9:1)\\
OXD5 &
  216.06 &
  217-219 &
  Yellowish oily liquid &
  65.7 &
  0.74 &
  \multicolumn{1}{p{\dimexpr(.16219999999999995\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Ethyl acetate: ethanol (7:3)}}\\
OXD6 &
  244.09 &
  220-222 &
  Yellowish oily liquid &
  68.8 &
  0.84 &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Chemicals}

 Valeric acid, BDH, UK, Ethylbromide, standard Sigma-Aldrich German, 


  
  \begin{enumerate}
  \item \relax Butyl bromide, sigma {\textendash}aldrich German. 
  \item \relax Pentyle bromide, sigma {\textendash}aldrich
  \item \relax Benzyl bromide, BDH M/231/202LTD 12526 Cas98-142-2. 
  \item \relax Sulphoric acid 99\%, Aldrich 49/1586-LTD. 
  \item \relax Hydrochloric acid 36\%, BDH Chem. LTD. 
  \item \relax n-Hexane, BDH M/405/9 LTD. 
  \item \relax Bromo ethyl acetate, sigma {\textendash}aldrich, 
  \item \relax Absolute ethanol and methanol, sigma {\textendash}aldrich pvt., Ltd., Bengaluru, India. 
  \item \relax Sodium hydroxide and ethyle acetate, Merck, Germany. 
  \item \relax Hydrazine hydrate 99.5\%, ALPHA company, India.
  \item \relax Sodium acetate, Fluka switizland.
  \item \relax Nutrient agar
  \item \relax Nutrient broth, OXOID, England.
  \item \relax Mueller-Hinton agar, CDH, India
  \end{enumerate}
  \textbf{Synthesis of the compound}

The starting materials ethyl valerate and valeric acid hydrazide were prepared according to the literatures \unskip~\citep{582641:13494100,582641:13494101}.

\textbf{Synthesis of 1,3,4-oxadiazole}

To a solution containing 95\% ethanol and 4 g (0.1 mole) of sodium hydroxide (dissolved in the least amount of water), 11.6 g (0.1 mole) of valeric hydrazide was added, followed by 9.4 ml (0.15 mole) of carbon disulfide. The reaction mixture was heated under reflux for 3hr till all the evolution of hydrogen sulfide ceased \unskip~\citep{582641:13494102}. The resulting mixture was diluted with water and acidified with diluted hydrochloric acid containing ice. The reaction mixture was allowed to stand at the ice bath for 30 minutes. The mixture was poured to a separation funnel, where chloroform used to extract the product. The organic layer separated and evaporated to obtain the product. The characterizations of the product are listed in Table~\ref{tw-7f6e25aedf3c}.


\bgroup
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\centering \makeatletter\IfFileExists{images/b0dc4d77-de1c-4d76-ab69-e7be12023587-u1.png}{\includegraphics{images/b0dc4d77-de1c-4d76-ab69-e7be12023587-u1.png}}{}
\makeatother 
\caption{\boldmath {Synthesis pathway for series compounds; OXD1 to OXD6}}
\label{f-ac01aca0d10f}
\end{scheme}
\egroup
\textbf{Synthesis of Mercaptoalkyl 1,3,4-Oxidiazole and Mercaptocarboxylic acid}

All compounds; 2  -butyl-5-(ethylthio)-1,3,4-oxadiazole (OXD1), 2  -butyl-5-(butylthio)-1,3,4-oxadiazole (OXD2), 2  -butyl-5-(pentylthio)-1,3,4-oxadiazole (OXD3), and 2  - ((5-butyl-1,3,4-oxadiazol-2-yl)thio)acetic acid (OXD5), were prepared by the same method and listed in the Table~\ref{tw-ea21308882d0}. 

A mixture of 0.015 mole of OXD 0.018 mole of alkyl bromides (ethyl bromide, bentyl bromide, or monobromoacetic acid) and 0.02 mole of sodium acetate in 50 ml of ethanol was heated under reflux for 3 hr., then allowed to cool, and poured into 100 ml of cold water containing ice. The mixture was poured to a separation funnel, where chloroform used to extract the product \unskip~\citep{582641:13494103}. Then the organic layer separated and evaporated to obtain the product. The characterizations of the products are listed in Table~\ref{tw-7f6e25aedf3c}.

\textbf{Synthesis of 2  -Benzyl-5-Butyl-1,3,4-Oxadiazole}

To a solution of 1.58g (0.01 mole) of OXD and 4.1g (0.05 mole) of sodium acetate in 30 ml of absolute ethanol,1.9 ml ( 0.01 mole) of benzyl bromide was added \unskip~\citep{582641:13494104}. The reaction mixture was refluxed for 4 hrs. The content was then poured into crushed ice, and the mixture was transferred to a separation funnel, where chloroform used to extract the product. Then the organic layer separated and evaporated to obtain the product. The characterizations of the product are listed in Table~\ref{tw-7f6e25aedf3c} -Table~\ref{tw-23e6a13f088b}.

\textbf{Synthesis of Ethyle 2-(5-Butyl-1,3,4-Oxadiazol-2-yl)] Acetat }

A solution of 3.5 g (0.01 mole) of OXD and 1.2 g (0.01 mole) of sodium hydroxide in 30 ml of absolute ethanol was heated under reflux for 30 minutes. A 0.01 mole ethyl bromoacetate was added, and the resulting mixture was refluxed for 4 hrs. After cooling, the solution was poured on ice, and the mixture was transferred to a separation funnel, where chloroform used to extract the product \unskip~\citep{582641:13494105}. Then the organic layer separated and evaporated to obtain the product. The characterizations of the product are listed in Table~\ref{tw-7f6e25aedf3c}.


\bgroup
\fixFloatSize{images/b301e861-d719-4066-96d6-ac4abcfb5a40-upicture2.png}
\begin{scheme}[!htbp]
\centering \makeatletter\IfFileExists{images/b301e861-d719-4066-96d6-ac4abcfb5a40-upicture2.png}{\includegraphics{images/b301e861-d719-4066-96d6-ac4abcfb5a40-upicture2.png}}{}
\makeatother 
\caption{\boldmath {The structure of OXD}}
\label{f-d7c05de969a3}
\end{scheme}
\egroup

\bgroup
\fixFloatSize{images/d6522aa8-512a-4d30-847a-29cb87308f34-upicture3.png}
\begin{scheme}[!htbp]
\centering \makeatletter\IfFileExists{images/d6522aa8-512a-4d30-847a-29cb87308f34-upicture3.png}{\includegraphics{images/d6522aa8-512a-4d30-847a-29cb87308f34-upicture3.png}}{}
\makeatother 
\caption{\boldmath {The structure of OXD1}}
\label{f-e27408009ae7}
\end{scheme}
\egroup

\bgroup
\fixFloatSize{images/d9019811-8720-4bff-87e8-86537167f90a-upicture4.png}
\begin{scheme}[!htbp]
\centering \makeatletter\IfFileExists{images/d9019811-8720-4bff-87e8-86537167f90a-upicture4.png}{\includegraphics{images/d9019811-8720-4bff-87e8-86537167f90a-upicture4.png}}{}
\makeatother 
\caption{\boldmath {The structure of OXD2 }}
\label{f-5e65b8d81bec}
\end{scheme}
\egroup

\bgroup
\fixFloatSize{images/f05f2e51-1815-4e0a-96d8-fea30319b20c-upicture5.png}
\begin{scheme}[!htbp]
\centering \makeatletter\IfFileExists{images/f05f2e51-1815-4e0a-96d8-fea30319b20c-upicture5.png}{\includegraphics{images/f05f2e51-1815-4e0a-96d8-fea30319b20c-upicture5.png}}{}
\makeatother 
\caption{\boldmath {The structure of OXD3 }}
\label{f-461f2c35733e}
\end{scheme}
\egroup

\bgroup
\fixFloatSize{images/418c1077-1992-41b4-9ad9-77952aab9010-upicture6.png}
\begin{scheme}[!htbp]
\centering \makeatletter\IfFileExists{images/418c1077-1992-41b4-9ad9-77952aab9010-upicture6.png}{\includegraphics{images/418c1077-1992-41b4-9ad9-77952aab9010-upicture6.png}}{}
\makeatother 
\caption{\boldmath {The structure of OXD4 }}
\label{f-e39141310967}
\end{scheme}
\egroup

\bgroup
\fixFloatSize{images/8c2dcccf-d451-48ab-8793-9af045a8ac39-upicture7.png}
\begin{scheme}[!htbp]
\centering \makeatletter\IfFileExists{images/8c2dcccf-d451-48ab-8793-9af045a8ac39-upicture7.png}{\includegraphics{images/8c2dcccf-d451-48ab-8793-9af045a8ac39-upicture7.png}}{}
\makeatother 
\caption{\boldmath {The structure of OXD5}}
\label{f-9cf307927266}
\end{scheme}
\egroup

\bgroup
\fixFloatSize{images/a5f7e60a-3b71-4d25-b901-b5a74e730765-upicture8.png}
\begin{scheme}[!htbp]
\centering \makeatletter\IfFileExists{images/a5f7e60a-3b71-4d25-b901-b5a74e730765-upicture8.png}{\includegraphics{images/a5f7e60a-3b71-4d25-b901-b5a74e730765-upicture8.png}}{}
\makeatother 
\caption{\boldmath {The structure of OXD6 }}
\label{f-08921a55a7a5}
\end{scheme}
\egroup

    
\section{Results and Discussion}
The study involves synthesis of new 1,3,4 oxidiazole from valeric acid, which followed by synthesis s-substitution oxidiazole derivative as shown in Scheme~\ref{f-ac01aca0d10f}. Sulfur act as nucleic substituted for different alkyl carbon of R-X in preparation of mercapto substituted 1,3,4 Oxidiazole \unskip~\citep{582641:13494106}.


\begin{table*}[!htbp]
\caption{\boldmath {C.H.N. data of valeric-ester and hydrazide} }
\label{tw-23e6a13f088b}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.10098571428571427\linewidth-2\tabcolsep}p{\dimexpr.1597857142857143\linewidth-2\tabcolsep}p{\dimexpr.1896857142857143\linewidth-2\tabcolsep}p{\dimexpr.26098571428571425\linewidth-2\tabcolsep}p{\dimexpr.10458571428571428\linewidth-2\tabcolsep}p{\dimexpr.09438571428571429\linewidth-2\tabcolsep}p{\dimexpr.08958571428571428\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Compd. & Molecular formula  & Molecular weight  & Observed and Calculated  & C  & H  & N\\
\tblmidrule 
\multicolumn{1}{p{\dimexpr(.10098571428571427\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{VE }} &
  \multicolumn{1}{p{\dimexpr(.1597857142857143\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{7}}H\ensuremath{_{14}}O\ensuremath{_{2\ }}}} &
  \multicolumn{1}{p{\dimexpr(.1896857142857143\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{130.19 }} &
  Observed &
  64.31 &
  10.73 &
  \\
 &
   &
   &
  Calculated &
  64.58 &
  10.84 &
  \\
\multicolumn{1}{p{\dimexpr(.10098571428571427\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{HZ }} &
  \multicolumn{1}{p{\dimexpr(.1597857142857143\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{5}}H\ensuremath{_{12}}N\ensuremath{_{2}}O}} &
  \multicolumn{1}{p{\dimexpr(.1896857142857143\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{116.16}} &
  Observed &
  51.58 &
  10.32 &
  23.89\\
 &
   &
   &
  Calculated &
  51.7 &
  10.41 &
  24.12\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {C.H.N.S data of valeric-OXD derivatives} }
\label{tw-63b4837a3f1a}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0802\linewidth-2\tabcolsep}p{\dimexpr.13820000000000002\linewidth-2\tabcolsep}p{\dimexpr.1373\linewidth-2\tabcolsep}p{\dimexpr.1675\linewidth-2\tabcolsep}p{\dimexpr.1045\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}p{\dimexpr.1157\linewidth-2\tabcolsep}p{\dimexpr.1366\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Compd. & Molecular formula  & Molecular weight  & Observed and Calculated  & C\%  & H\%  & N\%  & S\% \\
\tblmidrule 
\multicolumn{1}{p{\dimexpr(.0802\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{OXD }} &
  \multicolumn{1}{p{\dimexpr(.13820000000000002\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{6}}H\ensuremath{_{16}}N\ensuremath{_{2}}O\ensuremath{_{3}}S}} &
  \multicolumn{1}{p{\dimexpr(.1373\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{158.05}} &
  Observed  &
  45.18  &
    6.11 &
  17.37 &
  19.92\\
 &
   &
   &
  Calculated &
  45.55 &
  6.37 &
  17.71 &
  20.26\\
\multicolumn{1}{p{\dimexpr(.0802\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{OXD1 }} &
  \multicolumn{1}{p{\dimexpr(.13820000000000002\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{8}}H\ensuremath{_{14}}N\ensuremath{_{2}}OS}} &
  \multicolumn{1}{p{\dimexpr(.1373\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{186.27}} &
  Observed &
  51.91 &
  7.44 &
  15.49 &
  17.67\\
 &
   &
   &
  Calculated &
  51.58 &
  7.58 &
  15.04 &
  17.21\\
\multicolumn{1}{p{\dimexpr(.0802\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{OXD2 }} &
  \multicolumn{1}{p{\dimexpr(.13820000000000002\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{10}}H\ensuremath{_{18}}N\ensuremath{_{2}}OS}} &
  \multicolumn{1}{p{\dimexpr(.1373\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{182.14}} &
  Observed &
  55.73 &
  4.67 &
  13.44 &
  15.33\\
 &
   &
   &
  Calculated &
  56.04 &
  8.47 &
  13.07 &
  14.96\\
\multicolumn{1}{p{\dimexpr(.0802\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{OXD3 }} &
  \multicolumn{1}{p{\dimexpr(.13820000000000002\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{12}}H\ensuremath{_{22}}N\ensuremath{_{2}}OS}} &
  \multicolumn{1}{p{\dimexpr(.1373\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{192.16}} &
  Observed &
  59.91 &
  8.96 &
  11.87 &
  12.84\\
 &
   &
   &
  Calculated &
  59.47 &
  9.15 &
  11.56 &
  13.23\\
\multicolumn{1}{p{\dimexpr(.0802\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{OXD4 }} &
  \multicolumn{1}{p{\dimexpr(.13820000000000002\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{13}}H\ensuremath{_{16}}N\ensuremath{_{2}}OS}} &
  \multicolumn{1}{p{\dimexpr(.1373\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{213.16}} &
  Observed &
  63.12 &
  6.77 &
  10.88 &
  13.38\\
 &
   &
   &
  Calculated &
  62.87 &
  6.49 &
  11.28 &
  12.91\\
\multicolumn{1}{p{\dimexpr(.0802\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{OXD5 }} &
  \multicolumn{1}{p{\dimexpr(.13820000000000002\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{8}}H\ensuremath{_{12}}N\ensuremath{_{2}}OS}} &
  \multicolumn{1}{p{\dimexpr(.1373\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{216.06}} &
  Observed &
  44.92 &
  5.33 &
  13.25 &
  14.45\\
 &
   &
   &
  Calculated &
  44.43 &
  5.59 &
  12.95 &
  14.83\\
\multicolumn{1}{p{\dimexpr(.0802\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{OXD6 }} &
  \multicolumn{1}{p{\dimexpr(.13820000000000002\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{C\ensuremath{_{10}}H\ensuremath{_{16}}N\ensuremath{_{2}}O\ensuremath{_{3}}S}} &
  \multicolumn{1}{p{\dimexpr(.1373\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{244.09}} &
  Observed  &
    48.88 &
  6.45 &
  11.91 &
  13.56\\
 &
   &
   &
  Calculated &
  49.16 &
  6.6 &
  11.47 &
  13.12\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Inhibition zone of tested compounds and standard drugs} }
\label{tw-016e8edf507b}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.2132\linewidth-2\tabcolsep}p{\dimexpr.1868\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}s.aureus  & P.aeruginosa  & E.coli  & Conc. (\ensuremath{\mu}g/ml)  & Compounds \\
\tblmidrule 
0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 &
   50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  OXD\\
6 \mbox{}\protect\newline 6  \mbox{}\protect\newline 8   \mbox{}\protect\newline 8  \mbox{}\protect\newline 10 &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 &
   50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  OXD1 \\
6 \mbox{}\protect\newline 6 \mbox{}\protect\newline 7 \mbox{}\protect\newline 11 \mbox{}\protect\newline 12  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 &
   50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  OXD2 \\
0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 10 \mbox{}\protect\newline 12 \mbox{}\protect\newline 15  &
  0  \mbox{}\protect\newline  0  \mbox{}\protect\newline 10 \mbox{}\protect\newline 12 \mbox{}\protect\newline 15  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 &
   50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  OXD3 \\
6 \mbox{}\protect\newline 6 \mbox{}\protect\newline 9 \mbox{}\protect\newline 11 \mbox{}\protect\newline 12  &
   5 \mbox{}\protect\newline 7 \mbox{}\protect\newline 8 \mbox{}\protect\newline 11 \mbox{}\protect\newline 14  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 &
   50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  OXD4 \\
6 \mbox{}\protect\newline 7 \mbox{}\protect\newline 5 \mbox{}\protect\newline 8 \mbox{}\protect\newline 19  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 6 \mbox{}\protect\newline 10 \mbox{}\protect\newline 12  &
   50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  OXD5 \\
0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 8 \mbox{}\protect\newline 13 \mbox{}\protect\newline 18  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 10 \mbox{}\protect\newline 13 \mbox{}\protect\newline 17  &
   50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  OXD6 \\
0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 6 \mbox{}\protect\newline 8 &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 15  &
  50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  Amoxicillin\\
0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  &
  0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  \mbox{}\protect\newline 0  &
  8 \mbox{}\protect\newline 12 \mbox{}\protect\newline 15 \mbox{}\protect\newline 18 \mbox{}\protect\newline 20 &
  50 \mbox{}\protect\newline 125 \mbox{}\protect\newline 250 \mbox{}\protect\newline 500 \mbox{}\protect\newline 1000  &
  Cefepime\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
The hydrazides undergo cyclization reaction by CS\ensuremath{_{2}} in alcoholic sodium hydroxide and the release of hydrogen disulfide gas to give 1,3,4-oxadiazzole-2-thiol IV. The compound IV reacted with diverse compounds to give mercaptosubstituted-OXD . These reactions involved sulfur nucleophilic substitution (an attack by SH) at the alkyl carbon of different R-X, as shown in Scheme~\ref{f-ac01aca0d10f}. 

 The cyclization of compound III, to form compound IV, involved the nucleophilic attack of the enol form of hydrazide at carbon disulfide to form xanthate salt, the intranucleophilic addition of amino group and losing the hydrogen disulfide to form sodium-OXD ion which was converted to OXD-thiol in acidic medium \unskip~\citep{582641:13494107,582641:13494108,582641:13494109,582641:13494110,582641:13494111,582641:13494112,582641:13494113}.\textbf{\space }

\textbf{FT}-\textbf{IR spectrum of OXD}

The IR spectra for all OXD performed by the KBr disc method. FT-IR spectra for all studied compounds were measured as KBr disks using FT-IR 8400S SHIMADZU (Japan), in the technique Laboratory of Pharmaceutical Chemistry Department / College of Pharmacy / Basra University.

\textbf{\textbf{FT}-\textbf{IR spectrum of OXD}}

The compound non substituted (OXD) showed absorption band at 2777 cm\ensuremath{^{-1 }} which characteristic of S-H stretching. While this band disappear in substituted derivative S-R, strong-medium band absorption 2870-2958 cm\ensuremath{^{-1}} attributed to C-H stretching of aliphatic. Also a strong band absorption at 1620 which characteristic of C=N stretching. Medium absorption band at 1165 cm\ensuremath{^{-1}} which attributed to C-O stretching and strong absorption band at 1481 cm\ensuremath{^{-1}} which attributed to C-H bending.

\textbf{FT}-\textbf{IR spectrum of OXD1 } \textbf{\space }

The compound (OXD1) show strong absorption band at 1620cm\ensuremath{^{-1}} refer to C=N stretching, the medium-strong band 2870-2958 cm\ensuremath{^{-1}} attributed C-H stretching of aliphatic alkyl, strong band at 1489 cm\ensuremath{^{-1}} refer to \-C-H bending, medium band 1161 cm\ensuremath{^{-1}} attributed to C-O stretching. 

\textbf{FT}-\textbf{IR spectrum of OXD2} \textbf{\space }

The compound(OXD2) show strong absorption band at 1613cm\ensuremath{^{-1}} refer to C=N stretching, the medium-strong band 2870-2960 cm\ensuremath{^{-1}} attributed C-H stretching of aliphatic alkyl, strong band at 1483 cm\ensuremath{^{-1}} refer to \-C-H bending, medium band 1155 cm\ensuremath{^{-1}} attributed to C-O stretching.

\textbf{FT}-\textbf{IR spectrum of OXD3} \textbf{\space }

The compound(OXD3) show strong absorption band at 1618 cm\ensuremath{^{-1}} refer to C =N stretching, the medium-strong band 2868-2958 cm\ensuremath{^{-1}} attributed C-H stretching of aliphatic alkyl, strong band at 1483 cm\ensuremath{^{-1}} refer to \-C-H bending, medium band 1155 cm\ensuremath{^{-1-}}which characteristic to C-O stretching.

\textbf{FT}-\textbf{IR spectrum of OXD4} \textbf{\space }

The compound (OXD4) show strong absorption band at 1620cm\ensuremath{^{-1}} refer to C=N stretching, medium band at 3065 cm\ensuremath{^{-1-}}which characteristics of C-H aromatic, medium-strong band 2873-2958 cm\ensuremath{^{-1}} attributed C-H stretching of aliphatic alkyl, strong band at 1458 cm\ensuremath{^{-1}} refer to \-C-H bending, medium band 1130 cm\ensuremath{^{-1}}\ensuremath{^{-}}which characteristic to C-O stretching.

\textbf{FT}-\textbf{IR spectrum of OXD5} \textbf{\space }

The compound (OXD5) was characterized by a strong absorption band at 1720 cm\ensuremath{^{-1}} which attributed C=O stretching of the carboxylic acid in this compound and also showed a broadband in the range 3153 cm\ensuremath{^{-1}} which is characteristic of O-H stretching that appeared at lower frequency due to strong intermolecular hydrogen bonding, strong absorption band at 1620 cm\ensuremath{^{-1}} refer to C=N stretching, medium-strong band 2872-2935 cm\ensuremath{^{-1}} attributed C-H stretching of aliphatic alkyl, strong band at 1379 cm\ensuremath{^{-1}} refer to \-C-H bending, medium band 1163 cm\ensuremath{^{-1}} which characteristic to C-O stretching.

\textbf{FT}-\textbf{IR spectrum of OXD6} \textbf{\space }

The compound (OXD6) was characterized by a strong absorption band at 1741cm\ensuremath{^{-1}} which attributed C =O stretching and this absorption band of carbonyl group gave good indication about formation of the of ester, strong absorption band at 1620 cm\ensuremath{^{-1}} refer to C=N stretching, medium-strong band 2872-2960 cm\ensuremath{^{-1}} attributed C-H stretching of aliphatic alkyl, strong band at 1489 cm\ensuremath{^{-1}} refer to \-C-H bending, medium band 1155cm\ensuremath{^{-1}} which characteristic to C-O stretching \unskip~\citep{582641:13494114,582641:13494115,582641:13494116,582641:13494117}. 

\ensuremath{^{\textbf{1}}} \textbf{H-NMR Spectrum}

The studied compounds were performed at the analytical Laboratory of Tehran University/College of sciences/ Chemistry department, use 500MHz NMR (INOVA Switzerland). DMSO-d\ensuremath{_{6}} was used as a solvent and TMS as an internal standard. 

\ensuremath{^{\textbf{1}}}\textbf{H-NMR Spectrum of prepared OXD compounds} \textbf{\space }

\ensuremath{^{1}}H-NMR spectrum of prepared OXD derivatives were performed in deuterated dimethyl sulfoxide solutions with tetramethylsaline as an internal standard. The represent the \ensuremath{^{1}}H-NMR spectra of the OXD derivatives. All these spectra showed a peak at 2.5 ppm, which was due to DMSO solvent, and some spectra showed a sharp peak at 3.33 ppm due to dissolved water in DMSO.

\ensuremath{^{\textbf{1}}} \textbf{H-NMR Spectrum of OXD }

The \ensuremath{^{1}}HNMR spectrum of compound OXD displayed characteristic aliphatic signals of alkyl chain protons represented by the following, triplet signal at 0.801 ppm related to protons of -CH\ensuremath{_{3\ }} group, 1.267 ppm as sixtet related to -CH\ensuremath{_{2}}-\ensuremath{_{}} beside -CH\ensuremath{_{3}}, another signal at 1.532 ppm related to -CH\ensuremath{_{2}}- (-CH\ensuremath{_{2}}CH\ensuremath{_{2}}CH\ensuremath{_{3}}), last signal at 2.469 ppm related to {\textendash}CH\ensuremath{_{2}}- beside oxadiazole ring, as shown in Scheme~\ref{f-d7c05de969a3}.

\ensuremath{^{\textbf{1}}} \textbf{H-NMR Spectrum of OXD1 }

The \ensuremath{^{1}}HNMR spectrum of compound OXD1 (Scheme~\ref{f-e27408009ae7}) showed aliphatic signals at 0.851 ppm as \textit{triplet } related to three protons of -CH\ensuremath{_{3}} (CH\ensuremath{_{3}}CH\ensuremath{_{2}}CH\ensuremath{_{2}}CH\ensuremath{_{2}}-), \textit{sixtet } signal at 1.337 ppm\textit{} related to (CH\ensuremath{_{2}}) adjacent to CH\ensuremath{_{3}} and CH2, another signal \textit{pentet } at 1.656 ppm characteristic to protons (-CH\ensuremath{_{2}}) which between CH\ensuremath{_{2}} and CH\ensuremath{_{2}} , also there is \textit{triplet} signal at 1.371 attributed to CH\ensuremath{_{2}} adjacent to oxidiazole ring. There is another aliphatic system referred to mercaptoethyl moiety which gave two signals, the first showed as \textit{triplet } at 2.734 ppm and the second as \textit{quartet} at 3.146\textit{\space } and related to(-CH\ensuremath{_{3}}) and (-CH\ensuremath{_{2}}-S-) respectively.

\ensuremath{^{\textbf{1}}}\textbf{H-NMR Spectrum OXD2 } \textbf{\space }

The \ensuremath{^{1}}HNMR spectrum of compound OXD  2 (Scheme~\ref{f-5e65b8d81bec}) illustrated two triplet signals at 0.73ppm, and 0.83 ppm are mainly resulting from the presence of six protons of terminated methyl groups , two sixtet signals at 1.2 ppm and 1.295 ppm related to two groups, the first methylene group 2 and the second for methylene group 7, another two pentet signals at 1.33 ppm and 1.38 ppm refer to two -CH\ensuremath{_{2}}- groups which are no.3 and no.6 respectively, the last two triplet signals at 2.94 ppm and 3 ppm characteristic of two methylene groups one adjacent to oxidiazole ring moiety and other is beside sulfur atom. 

\ensuremath{^{\textbf{1}}}\textbf{H-NMR Spectrum OXD3 } \textbf{\space }

The \ensuremath{^{1}}HNMR spectra of compound OXD3 (Scheme~\ref{f-461f2c35733e}) showed characteristic two \textit{  triplet } signals at 0.874 ppm and 0.891 ppm related to six protons of terminated two methyl groups,\textit{ multiplet} signals in the range 1.289-1.307ppm related to six protons of three methylene groups (5,6 and 7). Another multiplet signals in the range between 1.321-1.350 ppm related to four protons of two methylene groups 3 and 4, triplet signal at 2.762 ppm related to two protons of {\textendash}CH\ensuremath{_{2}}- beside oxadiazole moiety (2). The last signal at 1.160ppm is triplet related to protons of a methylene group(-CH\ensuremath{_{2}}-S-), which apparent downfield because of deshielded of a sulfur atom compared with signal methylene group ( no. 2).

\ensuremath{^{\textbf{1}}} \textbf{H-NMR Spectrum OXD4}

The \ensuremath{^{1}}HNMR spectrum of compound OXD4 (Scheme~\ref{f-e39141310967}) gave the following signals, triplet signal at 1.388ppm related to three protons of terminated methyl group, sixtet signal at 1.380 characteristic of two protons of methylene group which between {\textendash}CH\ensuremath{_{3}}- and {\textendash}CH\ensuremath{_{2}}-, pentet signals at 1.711ppm related to methylene group between {\textendash}CH\ensuremath{_{2}}- and {\textendash}CH\ensuremath{_{2}}-, triplet signal at 2.782 ppm related methylene group adjacent to oxidiazole ring moiety, a singlet signal at 5.098 ppm which a good distinguish feature related to methylene group beside sulfur atom, the last characteristic multiplet signals in the range 7.305 {\textendash} 7.322ppm related to five protons of phenol ring.

\ensuremath{^{\textbf{1}}}\textbf{H-NMR Spectrum OXD5} \textbf{\space }

The \ensuremath{^{1}}HNMR spectra of compound OXD5 (Scheme~\ref{f-9cf307927266}) showed characteristic triplet signal at 0.93ppm related to three protons of terminated methyl group, sixtet signal at 1.36 ppm referred to the two protons of -CH\ensuremath{_{2}}- which between -CH\ensuremath{_{3}}- and -CH\ensuremath{_{2}}-, another signal as pentet at 1.64 ppm attributed to -CH\ensuremath{_{2}}- between two methylene groups, also there is triplet signal at 2.29 ppm related to -CH2- adjacent to oxidiazole ring moiety, a singlet signal at 4.35 ppm related to methylene group adjacent to carbonyl group. 

\ensuremath{^{\textbf{1}}}\textbf{H-NMR Spectrum OXD6} \textbf{\space }

The \ensuremath{^{1}}HNMR spectra of compound OXD  6 (Scheme~\ref{f-08921a55a7a5}) displayed characteristic aliphatic system represented by   triplet signal at 1.196 ppm related to three protons of terminated methyl group which beside oxidiazole moiety , sixtet signal at 1.268 ppm which attributed to -CH\ensuremath{_{2}} between CH\ensuremath{_{3}} and -CH\ensuremath{_{2}}, two protons of methylene groups gave pentet signal at 1.376 ppm related to -CH\ensuremath{_{2}}- group between two methylene groups, another signal which is triplet at 2.758 ppm related to -CH\ensuremath{_{2}}- beside oxidiazole side, also there is singlet signal at 4.137 ppm related to methylene group between sulphur atom and carbonyl group, the last two signals at 4.160 ppm as triplet related to methyl group of ester and quartet signal at 4.175 ppm indicated methylene group which apparent at downfield because de shielded of oxygen atom \unskip~\citep{582641:13494118,582641:13494119}.

\textbf{C. H. N. Analysis}

Elemental analysis of prepared compounds the measured value in a good agreement with the calculated value shown in Table~\ref{tw-23e6a13f088b} and Table~\ref{tw-63b4837a3f1a}.

\textbf{Antibacterial activity }

All synthesized OXD derivative compounds were evaluated against certain kinds of Gram-positive bacteria (S. aureus) for their antibacterial activity, and Gram-negative bacteria (\textit{E. coli}) used the diffusion technique of the filter paper disk, measuring the diameter of the inhibition area after 24 hours. The preliminary findings showed that there were some active compounds against \textit{E. Coli} or and S\textit{. Aureus}, as shown in Table~\ref{tw-016e8edf507b}.

Most compounds prepared showed bacterial activity against Gram-negative and Gram-positive bacteria. Compound OXD gave no activity while OXD1, OXD2, OXD3, OXD4, OXD5, OXD6 show good bacterial activity against (\textit{Staphylococcus aureus}), and also OXD3 and OXD4 had good activity against resistant bacteria \textit{Pseudomonas aerogenosa.} While both standards drugs used did not gave activity against this bacteria. The acid and ester group of OXD5 and OXD6 respectively showed good bacterial activity at high concertation against Gram-negative  (\textit{E. coli}) and Gram-positive (\textit{S. aureus}).
    
\section{Conclusion}
The study included the synthesis of the new compounds 1,3,4-oxadiazole-2-thiol (OXD) series derived from valeric acid and followed by the synthesis of S-substituted-OXD. The synthesized compounds were tested as antibacterial agents against some microorganism (Gram-negative and Gram-positive strains) which gave good inhibition zone as compared with standard drugs. 
\section*{Acknowledgement}The authors thank the University of Basra, college of pharmacy and department of pharmaceutical chemistry for supporting this work.

\textbf{Contribution of authors}

 We declare that this work was done by the authors named in this article and all liabilities pertaining to claims relating to the content of this article will be borne by the authors. Suhail H. Derawey\textbf{\space }conceived and designed the study\textbf{. }Mazin N. Mosa designed all the experiments and revised the manuscript. Ekhlas Qanber Jasim and Rawaa M. O.Hraishawi performed the experiments, collected, analyzed the data, and wrote the manuscript. 
    

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