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\begin{document}


\def\RunningAuthor{Abdullah S. Asia et al.}
\firstPage{411}
\articleType{Original Article}
\receivedDate{05.07.2019}
\acceptedDate{22.10.2019}
\revisedDate{13.10.2019}
\journalVolume{2020, 11}
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\journalDoi{ijrps.v11i1.1835}
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\title{\textbf{Synthesis, characterization and antibacterial studies of Schiff bases of acyclovir}}
\author{Abood~S~Huda\textsuperscript{1},  
            Abdullah~S.~Asia\textsuperscript{*}\textsuperscript{2}, 
            Wrewish~S~Zainab\textsuperscript{3}~\\[5pt]{\textsuperscript{1}Department of pharmaceutical chemistry, Institute of Pharmacy, Basra, Iraq}~\\{\textsuperscript{2}Department of Pharmacology and Toxicology, Institute of Pharmacy, Basra, Iraq}~\\{\textsuperscript{3}Department of laboratory, Institute of Pharmacy, Basra, Iraq}}

\begin{abstract}
There is a crucial medical need for the progress of new antibacterial agents with new and more efficient mechanisms. Schiff bases are stated to have a wide range of pharmacological activities, including antimicrobial, antibacterial, antifungal, antioxidant, and anticancer activities, which are largely due to the distinguishing C=N group. Furthermore, heterocyclic compounds containing acyclic hydroxylated side chains, for example, acyclovir (ACV), are an essential class of antiviral acyclonucleosides. Therefore, this work was to synthesize and evaluate a new series of acyclovir analogues bearing a Schiff base moiety. Some of Schiff's bases synthesis in an ethanolic solution of drug, aldehydes, and glacial acetic acid as a catalyst followed in the synthesis of substituted acyclovir drug compounds. In this work, two new series of acyclovir analogues bearing a Schiff base moiety were Synthesised, characterized, and confirmed by various spectral techniques like FTIR, CHN, and 1HNMR spectra, in addition to melting point and retardation factor (Rf.). The biological activity of synthesized Schiff base compounds measured against a panel of various bacteria. The results revealed that these compounds showed antibacterial activity against Gram-positive bacteria such as \textit{bacillus} and Gram-negative bacteria such as \textit{proteus}, \textit{E-coli}, \textit{pseudomonas}, and \textit{klebsiella}. It concluded that synthesized Schiff base compounds showed higher antibacterial activity than acyclovir that they derived from it.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Schiff bases,\newline heterocyclic compounds,\newline acyclovir,\newline antibacterial activity
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Abdullah~S.~Asia~\\ Phone:\ 009647719532885~\\  Email:\ asia\_abdullah65@yahoo.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Increasing bacterial resistance to antibiotics associated with an increase in the mortality rate from infectious diseases. There is a crucial medical need for the progress of new antibacterial agents with new and more efficient mechanisms \unskip~\citep{623442:14578811}. Schiff bases supposed as promising antibacterial agents; Hugo Schiff first stated them in 1864. A Schiff's base compound contains azomethine group, which is a functional group that contains a carbon-nitrogen double bond -C=N- with the nitrogen atom attached to an aryl or alkyl group. The general formula of Schiff's bases is R\ensuremath{^{1}}R\ensuremath{^{2}}C=NR\ensuremath{^{3}}, where R side chain is an organic group resulted from condensation of ketones (or) aldehydes with primary amines \unskip~\citep{623442:14578816}. Schiff bases are stated to have a wide range of pharmacological activities including antimicrobial, antibacterial, antifungal, antipyretic, anti-inflammatory and anticancer activities, which are largely due to distinguishing C=N group \unskip~\citep{623442:14578805,623442:14578813,623442:14578810,623442:14578804}. Furthermore, heterocyclic compounds are widely used for the development of new and strong agents therapeutically important \unskip~\citep{623442:14578809}. Heterocyclic compounds containing acyclic hydroxylated side chains, for example, acyclovir (ACV), are an essential class of antiviral acyclonucleosides \unskip~\citep{623442:14578812}. Therefore, the design of heterocycles incorporates open-chain carbohydrate residues that takes a special interest in the spacious research objects that concentrate on modification of the acyclic side chain and/or heterocyclic base \unskip~\citep{623442:14578807}. The purpose of this work was to synthesize and evaluate new series of acyclovir analogues bearing a Schiff base moiety. 

Acyclovir is a selective and potent inhibitor of herpes viruses, and it extensively designated for the treatment of genital herpes, lips, and face cold sores, chicken pox, and shingles \unskip~\citep{623442:14578814}. Normally, this drug undergo phosphorylation by viral thymidine kinase into its monophosphate form. Acyclovir used as oral, parenteral, and topical dosage forms for the treatment of herpes infections \unskip~\citep{623442:14578808}. However, acyclovir have low skin permeability causes the topical dosage forms to be ineffective \unskip~\citep{623442:14578815}.
    
\section{Materials and Methods}
\textbf{Materials}

2-hdroxy-3-methoxy benzaldehyde, 4-hydroxy benzaldehyde, 2-hydroxy benzaldehyde, and ethanol obtained from Merck and Fluka. Ethyl acetate and nutrient agar obtained from LaB and Himedia. Analytical grade solvents from Merck used without further purification. The chemical liquids were distilled before use.

\textbf{Laboratory investigations}

The infrared spectra of all the compounds documented in the range 4000{\textendash}400 cm{\textendash}1 using a Shimadzu FTIR{\textendash}8400 spectrophotometer applying the KBr disc technique. The elemental The 1H NMR spectra were carried out in the university of Tehran recorded by Spectrometer Inova 500MHz. 


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\caption{\boldmath {The mechanism of the formation of Schiff base.}}
\label{f-003e24b0ed18}
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\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Physical properties of Schiff bases} }
\label{tw-ab1d0b38388e}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0692\linewidth-2\tabcolsep}p{\dimexpr.05610000000000001\linewidth-2\tabcolsep}p{\dimexpr.12170000000000002\linewidth-2\tabcolsep}p{\dimexpr.06379999999999998\linewidth-2\tabcolsep}p{\dimexpr.12150000000000002\linewidth-2\tabcolsep}p{\dimexpr.06690000000000001\linewidth-2\tabcolsep}p{\dimexpr.1454\linewidth-2\tabcolsep}p{\dimexpr.29\linewidth-2\tabcolsep}p{\dimexpr.0654\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Time of reaction & RF & TLC & Yield \mbox{}\protect\newline \% & Color and crystal form & MP \mbox{}\protect\newline (\ensuremath{^\circ}C) & Reactant compounds & IUPAC Name & symbol\\
\tblmidrule 
12 hrs. &
  0.60 &
  Chloroform: ethanol \mbox{}\protect\newline 7:3 &
  60\% &
  brown crystal &
  104-106 &
  Acyclovir +4-hydroxy benzaldehyde &
  (E)-2-((4-hydroxy benzylidene)amino)-9-((2-hydroxyethoxy)methyl)-1,9-dihydro-6H-purin-6-one &
  1\\
10 hrs. &
  0.36 &
  Hexane: ethanol \mbox{}\protect\newline 7:3 &
  73\% &
  Creamy crystal &
  76-77 &
  Acyclovir +2- hydroxyl- 4-methoxy benzaldehyde &
  (E)-2-amino-9-((2-hydroxyethoxy)methyl)-1,9-dihydro-6H-purin-6-one &
  2\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Schiff bases preparation 1 and 2}

\textbf{Synthesis of (E)-2- ((4-hydroxy benzylidene) amino) -9- ((2-hydroxyethoxy) methyl) -1, 9-dihydro -6H-purin-6-one 1}

A hot stirred solution of acyclovir (0.001mol, 0.225g), 40ml of ethanol (96\%) was added to 4-hydroxy benzaldehyde (0.001mol, 0.122g) were mixed in 250ml round bottom flask. To the reaction mixture (6 drops) of glacial acetic acid were added as a catalyst. The reaction was reflexed with stirrer for 12 hours, and the time reaction was tested by TLC. The mixture was cooled overnight. The precipitate was filtered and purified by recrystallization from methanol; its result is shown in Table~\ref{tw-ab1d0b38388e}.

\textbf{Synthesis of (E)-2-amino-9-((2-hydroxyethoxy) methyl)-1, 9-dihydro-6H-purin-6-one 2}

A hot stirred solution of acylovir (0.001mol. 0.225g), 40ml of ethanol (96\%), was added to 2-hydroxy-4-methoxy benzaldehyde (0.001mol. 0.152g) were mixed in 250ml round bottom flask. To the reaction mixture (8drops) of glacial acetic acid were added as a catalyst. The reaction was reflexed with stirrer for 9 hours, and TLC tested the time reaction. Then, the mixture was cooled overnight. The precipitate was filtered and purified by recrystallization from methanol. Its result is shown in Table~\ref{tw-ab1d0b38388e}.


\begin{table*}[!htbp]
\caption{\boldmath {Antibacterial activity data of Schiff bases of acyclovir drug (0.009 mg/ml)} }
\label{tw-c04802130d3d}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2257\linewidth-2\tabcolsep}p{\dimexpr.1427\linewidth-2\tabcolsep}p{\dimexpr.15200000000000003\linewidth-2\tabcolsep}p{\dimexpr.1196\linewidth-2\tabcolsep}p{\dimexpr.1992\linewidth-2\tabcolsep}p{\dimexpr.1608\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Compounds & \multicolumn{5}{p{\dimexpr(.7743\linewidth-2\tabcolsep)}}{\cAlignHack Zone of inhibition mm in diameter }\\
\rowcolor{kwdboxcolor}CompoundsDMSO (solvent) & Bacillus & Proteus & E- Coli & Pseudomonas & Klebsiella \mbox{}\protect\newline \\
\tblmidrule 
1 &
  10 &
  10 &
  9 &
  8 &
  -\\
2 &
  30 &
  28 &
  14 &
  12 &
  15\\
Acyclovir &
  - &
  - &
  - &
  - &
  -\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Compounds 1 and 2 are Schiff bases of acyclovir drug}
    
\item{(-) Lack of microbial growth inhibition}
\end{tablenotes}
\end{threeparttable}

\end{table*}
\textbf{Procedure for measurement of antibacterial activities of Schiff base compounds}

Kirby Bauer process was used with 6 mm diameter discs of filter paper, which were put in the autoclave apparatus at 100 \ensuremath{^\circ}C for 1 hr for sterilization under 1 atm. And kept in clean and sterilized glass screw plugs. The plate agar was diffused using Muller-Hinton agar with slight modification by (M.H.A) medium and was sterilized at 121 \ensuremath{^\circ}C for 15 minutes under 1 atm by autoclave apparatus and then poured after cooling into 11 cm sterilized Petri dishes.

The synthesized compounds tested for antibacterial activity using five microorganisms, including Gram-positive Bacillus and Gram-negative Escherichia coli (E- Coli), Proteus, Pseudomonas aeruginosa, and Klebsiella. Youth colonies of about 24hours of age obtained by streaking of the isolated bacteria on nutrient agar (N. A.). The discs saturated with the synthesized compounds (conc. 0.009 mg/ml) in DMSO (Dimethyl sulphoxide), added by clean forceps to (M.H.A.) medium, and formerly incubated for 24 hours at 37 \ensuremath{^\circ}C. After that, the dishes observed for the presence or absence of bacterial growth and the diameter of the zone where there is no bacterial growth around each disc measured in millimeters and the averages of inhibition zone diameters measured using Hahn method. This method based on antimicrobial efficiency by measuring the agent's zones of inhibition whose sizes are relative to the sensitivity of the organism to the particular antibiotic in the disc and the disc diffusion for testing chemical agents. Size of the inhibition zone correlated with the antimicrobial activity of the drug. 
    
\section{Results and Discussion}
The new series of acyclovir analogues bearing a Schiff base moiety were prepared and studied in this research. Schiff bases 1 and 2 were formed by the condensation reaction of some aldehydes such as 4-hydroxy benzaldehyde, 2-hydroxy-4-methoxybenzaldehyde and 2-hydroxy benzaldehyde with acyclovir drug in absolute ethanol with the elimination of water at the end of the reaction. As shown in the Scheme~\ref{f-003e24b0ed18}. 

The mechanism of the reaction, as illustrated in the Scheme~\ref{f-003e24b0ed18}, included the nucleophilic attack of an amine at the carbon atom of the carbonyl group.

\textbf{(E)-2-((4-hydroxybenzylidene) amino)-9-((2-hydroxyethoxy) methyl)-1, 9-dihydro-6H-purin-6-one }

FTIR (KBr) cm-1:3475 (OH alcohol) 3549 (OH phenol), 3178(NH), 1639(C=C), 2854(C-H aliphatic), 3024(C-H aromatic), 1719(C=O), 1660(C=N). NMR [CDCl3] 500MHz: H11 0.8[s, 2H], H12 1.27[s, 2H], H10 2.08[s, 2H, CH2], 3.46[C-HN], N-H1 9.78 [s, 1H], 6.48[HC=N], Ar-H (6.92-7.75) [m,3H], 5.34[s, OH alcohol], 10.60[s, OH phenol]. C15H15N5O7: C, 54.69, H, 4.58; N, 21.26.

\textbf{(E)-2-((2-hydroxy-4-methoxybenzylidene) amino)-9-((2-hydroxyethoxy) methyl)-1, 9-dihydro-6H-purin-6-one}

FTIR (KBr) cm-1:3479(OH alcohol) 3549 (OH phenol), 3244 (NH), 1589(C=C), 2854 (CH aliphatic), 3043(CH aromatic), 1725 (C=O), 1647 (C=N). NMR [CDCl3] 500MHz: H121.27 [t,2H,CH2], H111.35 [t,2H,CH2], OCH3 2.49[s,3H], H10 4.10[s, 2H, CH2], 4.11 [s, OH alcohol] [HC=N] 6.88, H8 6.91[s,1H], Ar-H (7.23-7.24)[m, 3H], N-H1 10.14[s,1H] 10.24[s, OH phenol]. C16H17N5O8: C, 53.49, H, 4.77; N, 19.47.

\textbf{Antibacterial activities}

The results of antibacterial effects of the synthesized compounds against five microorganisms including Gram-positive and Gram-negative bacteria using Hahn method revealed that the Schiff base 2 showed higher activity on Gram-positive bacteria, Bacillus with inhibition zone 30 mm and on Gram-negative bacteria, Proteus with inhibition zone 28mm compare with 1 shows little inhibition against these bacteria. In addition, Schiff base 2 showed higher activity than Schiff base 1 on other Gram-negative bacteria such as E- Coli, Pseudomonas, and Klebsiella, as illustrated in Table~\ref{tw-c04802130d3d}.
    
\section{Conclusions}
The novel series of acyclovir schiff bases synthesized by the chemical reaction of different aldehydes with acyclovir. The synthesized compounds tested for antibacterial activity using five microorganisms including Gram-positive Bacillus and Gram-negative Escherichia coli (E- Coli), Proteus, Pseudomonas aeruginosa and Klebsiella, by the use of nutrient agar medium and disc diffusion method with incubation at 37\ensuremath{\circ }C for 24 h. DMSO was used for the preparation of the test solutions. In general, the synthesized compounds have showed more antibacterial activity than acyclovir that they derived from it. Schiff base 2 showed higher activity on Gram-positive bacteria, Bacillus with inhibition zone 30 mm, and on Gram-negative bacteria, Proteus with inhibition zone 28mm compare with Schiff base 1. In addition, Schiff base 2 showed higher activity than Schiff base 1 on other Gram-negative bacteria such as \textit{E- Coli}, \textit{Pseudomonas}, and \textit{Klebsiella}. This may be related to the structure of Schiff base 2, which contains an additional methoxy group compared with Schiff base 1.

\textbf{Author's contribution }

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

\textbf{Fundings}

The authors declare that they did not receive any specific funding from agencies in the commercial, public, profit sectors.
    

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