INTRODUCTION:

Cytarabine, is cytosine arabinoside (ara-C), is a chemotherapeutic agent used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), non-Hodgkin's lymphoma, and chronic myelogenous leukemia (CML). It is administered via injection, under the skin, or into the cerebrospinal fluid. There is a pharmaceutical liposomal formulation for which there is tentative evidence of enhanced outcomes in lymphoma including the meninges[1].

An antiviral therapeutic use of cytarabine is in the treatment of herpetic keratitis, herpes zoster (shingles) and viral infections that is resistant toidoxuridine[2]. Cytarabine-5´-triphosphate acts by inhibiting viral DNA synthesis.[3]

The power of cytarabine molecule as it to generate the targeting pharmacologic - therapeutic action as anti cancer and antiviral is extensively restricted and highly limited due to their an emergent resistance that developing as soon as administration of cytarabine resulting in abolish it is action. The cytarabine an emergent resistance is rationalized by a list number of mechanism related to it is pharmacological action included: Resistance can occur due toof decreased activation or transport and elevated catabolic breakdown. Metabolic degradation within the GI tract give rise to poor bioavailability. The drug distributes rapidly thought the tissues and total body water with cerebrospinal fluid (CSF) levels reaching( 20% to 40%) of those in plasma.

Cytidine deaminase is the main catabolic enzyme responsible for the inactivation of cytarabine in the serum into the inactive uracilform.[4] Cytarabine-5´-monophosphate is deaminated via deoxycytidylate deaminase enzyme, producing the inactive uridine-5´-monophosphate analog.[5] Cytarabine-5´-triphosphate is a substrate for SAMDH1(SAM and HD domain involving deoxynucleoside triphosphate triphosphohydrolase 1)[6]. Furthermore, SAMHD1 has been exhibited to limit the efficacy of cytarabine drug efficacy in patients.[7] On the other hand, the pharmacokinetic parameters of cytarabine is questionable it is a polar nucleoside drug The drug has a short biological half-life biphasic:( 10 min, 1–3 hr), low stability and reduced bioavailability about 20% by oral administration. Overdosing of patients with continuous infusions may lead to cytotoxic adverse effects involving myelo suppression, leukopenia and a thrombocytopenia, nausea and vomiting anorexia, diarrhea, and mucositis. Neurotoxicity is usually showed as ataxia, lethargy, and confusion. An allergic often manifested in pediatric patients involves fever, myalgia, malaise, bone pain, skin rash, conjunctivitis, and chest pain[8].Thus, various prod rug strategies and delivery systems have been explored extensively to enhance the half-life, stability and delivery of cytarabine. Many derivatives of these drugs (involving amino acid, peptide, fatty acid and phosphates) have been synthesized and evaluated, as well as different delivery systems.[8]

Amines are generally considered to be amenable to derivatization reactions and thus provide a “synthetic handle” that can be exploited in chemical modifications. As a result, numerous prod rugs of amines have been evaluated in an effort to overcome formulation and delivery barriers, which include low aqueous solubility, toxicity of the vehicle, poor membrane permeability, chemical and metabolic instability, and lack of specificity.[9]

The prodrug strategy is defined as the temporary modification of a functional group of a drug in order to enhance its pharmaceutical utility. Sometimes the functional group of a drug is merely a handle for the introduction of a moiety that confers on the new entity some desirable pharmaceutical characteristic; more frequently, the group is intimately conjugated with the pharmaceutical deficiency and its masking directly. Of the commonly occurring drug functional groups, focuses greatest effort has been directed at temporarily masking the amino functionality. The most simply identified liability of candidate amino drugs is their tendency to ionize under physiological conditions, producing to poor membrane penetration via the passive diffusion. The impact of this is amplified for the major number of amino drugs that are desired to penetrate the blood brain barrier to reach their pharmacological targets in CNS . A second issue that can influence the development of amino drugs is instability. An example of this is the affinity of primary amines to undergo first-pass metabolism due to N-acetylation and oxidation by monoaminooxidase enzyme system (MAO.) [10]Schiff bases, are usually too easily hydrolyzed to be useful as amine prod rug. Nevertheless, in some particular cases they may be surprisingly stable and useful as they impart increased lipophilic to the parent amine and depress the pK a values[11]. The anticonvulsant progabide drug was prepared as a prod rug of γ-aminobutyric acid (GABA) since it crosses the blood brain barrier , while the free drug doesn't. The prod rug is converted to γ-aminobutiramide and GABA which are then trapped if produced in the brain. However, it might not be considered a true prodrug as it possesses intrinsic the rapeuticactivity .[12]

Chemically activated azomethine prod rugs of the reference histamine H3 receptor agonist R-α-methylhistamine have been designated and evaluated, as well as enzymatically activated prod rugs involving (amide, esters and carbamates). [13]The new compounds, being more lipophilic, have increase the oral absorption and improved blood brain barrier penetration than the parent drug.[14,15]

In our study we use cytarabine drug as nucleus to design new pro drug Schiff base derivatives of amino functionality of cytarabine with different aldehydes moiety to maximized the therapeutic anticancer and antiviral actions of cytarabine , expected to improve pharmacokinetics and minimized the cytotoxic effects .in addition to screen anti bacterial action of both cytarabine and it is pro drug new derivatives.

EXPERIMENTAL WORK:

All solvents have been used of an analytical grade. FT.I.R spectra were recorded on Shimadzu I.R-408 spectrophotometer. Elemental analysis was performed using a Perkin- Elmer 204E Instrument. ¹HNMR spectrum were recorded on Bruker 300MHz. Thin layer chromatography were performed on a silica- gel (Merck) SG- 40 and developed with the solvents mentioned, spots were visualized and noticed with Iodine vapor. Melting points were determined by capillary tube method by melting point apparatus SMP30 Stuart(UK).

General procedure for synthesis Schiff bases:

(60 mmol) of cytarabine, (60 mmol) of some aromatic analdehyde were dissolved in (30 mL) of methanol, then added few drops of glacial acetic acid. The resulting mixture was stirred at (80⁰C) for (18) hr. Then, the TLC showed that the reaction was completed by using (methanol: petroleum ether, 1:4). The solution was separated by using diethyl ether. The organic layers were dried over anhydrous MgSO4. Removal of the solvent under vacuum and recrystallized from ethanol. The percent yield, physical appearance, and Rf values were given in the following data.

Molecular Formula: C₁₈H₂₂N₄O₅

Elemental Analysis: C, 57.75; H, 5.92; N, 14.96

Found: C, 57.544; N, 14.88; H, 5.899;

m.p. 240-242 , yield 66%

IR (KBr disc, cm^-1): 3476, 3441, due to OH stretching, 3128 due to CH aromatic stretching, 2938, 2823due to CH aliphatic stretching, 1662 due to carbonyl group stretching, 1648 due to benzene ring stretching, 1598, 1579, 1479 due to C=N and C =C stretching, 1278, 1111, 1072 due to C-O stretching and 798 due to C-H bonding

¹HNMR (Chemical shifts,δ, ppm)), (DMSO-d6): 9.67(s, 1HC=N imine), 7.57(d, 1H-6, HC=N pyrimidine ring), 6.06(d, 1H-1^-, anomeric), 5.64 (d, 1H-5, HC=N pyrimidine ring), 5.42–5.43 (2^-OH or 3^-OH), 5.04(5^-OH),3.97(H-2^- or H-3^-), 3.88( s, H-3^- or H-2^-), 3.73–3.74(H-4^-), 3.58–3.59 (2H-5, 3.19), 3.12 due to (s,N-(CH3)₂, 7.21-7.89 ( m,Aryl C-H).

4-(4-methylbenzylideneamino) cytarabine (C2)

Molecular Formula: C₁₇H₁₉N₃O₅

Elemental Analysis: C, 59.12; H, 5.55; N, 12.17;

Found: C, 58.878; N, 11.988; H, 5.533;

m.p. 240-242, yield 60%

IR (KBr disc, cm^-1): 3471, 3440 due to OH stretching, 3108 due to CH aromatic stretching, 2944, 2834 due to CH stretching, 1666 due to carbonyl group stretching, 1622 due to benzene ring stretching, 1583, 1537, 1473 due to C=N and C =C stretching, 1287, 1113, 1070 due to C-O stretching and 797 due to C-H bonding.

· ¹HNMR (Chemical shifts, δ, ppm)), (DMSO-d6) : 9.68 (s, 1HC=N imine ), 7.67( d , 1H-6, HC=N pyrimidine ring), 6.08 (d, 1H-1^-, anomeric), 5.71 (d, 1H-5, HC=N pyrimidine ring), 5.41–5.42 (2^- OH or 3^-OH), 5.05 (5^-OH), 3.97 (H-2^- or H-3^-) , 3.79 ( s, H-3^- or H-2^- ), 3.74–3.75 (H-4^- ), 3.60–3.62 (2H-5, 3.19), 3.05 due to ( s, CH₃), 7.11-7.49 ( m, Aryl C-H).

4-(4-bromobenzylideneamino) cytarabine (C3)

Molecular Formula: C₁₆H₁₆BrN₃O₅

Elemental Analysis: C, 46.85; H, 3.93; N, 10.24;

Found: C, 46.771; N, 10.138; H, 3.889;

m.p. 240-242 , yield 60%

IR (KBr disc, cm^-1): 3469, 3417due to OH stretching, , 3130 due to CH aromatic stretching , 2960, 2374 due to CH stretching, 1671 due to carbonyl group stretching, 1638 due to benzene ring stretching, 1580, 1539, 1477 due to C=N and C =C stretching, 1276, 1119, 1070 due to C-O stretching and 798 due to C-H bonding.

· ¹HNMR (Chemical shifts, δ, ppm)), (DMSO-d6): 9.79 (s, 1HC=N imine ), 7.74( d, 1H-6, HC=N pyrimidine ring), 6.61 (d, 1H-1^-, anomeric), 5.71 (d, 1H-5, HC=N pyrimidine ring), 5.47–5.5 (2^- OH or 3^-OH), 5.07 (5^-OH), 3.93 (H-2^- or H-3^-), 3.79 ( s, H-3^- or H-2^- ), 3.76–3.77 (H-4^- ), 3.46–3. 5 (2H-5, 3.19), 7.31-7.66( m, Aryl C-H).

4-(4-hydroxybenzylideneamino) cytarabine (C4)

Molecular Formula: C₁₆H₁₇N₃O₆

Elemental Analysis: C, 55.33; H, 4.93; N, 12.10;

Found: C, 55.199; N, 11.099; H, 4.839;

m.p. 240-242 , yield 60%

IR (KBr disc, cm^-1): 3468, 3428 due to OH stretching, 3110 due to CH aromatic stretching, 2964, 2877 due to CH stretching, 1668 due to carbonyl group stretching, 1624due to benzene ring stretching, 1578, 1521, 1484 due to C=N and C =C stretching, 1278, 1116, 1070 due to C-O stretching and 796 due to C-H bonding.

· ¹HNMR (Chemical shifts,δ, ppm)), (DMSO-d6) : 9.66 (s, 1HC=N imine ), 7.65( d , 1H-6, HC=N pyrimidine ring), 6.06 (d, 1H-1^-, anomeric), 5.71 (d, 1H-5, HC=N pyrimidine ring), 5.42–5.43 (2^- OH or 3^-OH), 5.07 (5^-OH), 3.99 (H-2^- or H-3^-) , 3.77 ( s, H-3^- or H-2^- ), 3.72–3.73 (H-4^- ), 3.61–3.627 (2H-5), 7.41-8.69 ( m, Aryl C-H), 10.2 ( s, OH Aryl).

4-(4-hydroxy-3-methoxybenzylideneamino) cytarabine (C5)

Molecular Formula: C₁₇H₁₉N₃O₇

Elemental Analysis: C, 54.11; H, 5.08; N, 11.14

Found: C, 53.677; N, 11.008; H, 4.989

IR (KBr disc, cm^-1): 3480, 3440 due to OH stretching, 3116 due to CH aromatic stretching, 2940, 2877 due to CH stretching, 1667 due to carbonyl group stretching, 1633 due to benzene ring stretching, 1579, 1537, 1483 due to C=N and C =C stretching, 1284, 1117, 1070 due to C-O stretching and 798 due to C-H bonding.

¹HNMR (Chemical shifts, δ, ppm)), (DMSO-d6) : 9.69 (s, 1HC=N imine ), 7.66( d, 1H-6, HC=N pyrimidine ring), 6.08 (d, 1H-1^-, anomeric), 5.73 (d, 1H-5, HC=N pyrimidine ring), 5.43–5.444 (2^- OH or 3^-OH), 5.06 (5^-OH), 3.976 (H-2^- or H-3^-) , 3.766 ( s, H-3^- or H-2^- ), 3.72–3.73 (H-4^- ), 3.61–3.62 (2H-5), 6.98-7.61 ( m, Aryl C-H), 9.42 ( s, OH Aryl), 3.88 ( s, O-CH₃).

4-(4-methoxybenzylideneamino) cytarabine (C6)

Molecular Formula: C₁₇H₁₉N₃O₆

Elemental Analysis: C, 56.51; H, 5.30; N, 11.63

Found: C, 56.444; N, 11. 558; H, 5.289

m.p. 240-242, yield 60%

IR (KBr disc, cm^-1): 3487, 3432 due to OH stretching, 3122 due to CH aromatic stretching, 2948, 2866 due to CH stretching, 1671 due to carbonyl group stretching, 1629 due to benzene ring stretching, 1578, 1539, 1481 due to C=N and C =C stretching, 1280, 1111, 1073 due to C-O stretching and 799 due to C-H bonding.

¹HNMR (Chemical shifts, δ, ppm)), (DMSO-d6): 9.65( s, 1HC=N imine ), 7.67( d , 1H-6, HC=N pyrimidine ring), 6.08 (d, 1H-1^-, anomeric), 5.72 (d, 1H-5, HC=N pyrimidine ring), 5.43–5.44(2^- OH or 3^-OH), 5.05 (5^-OH), 3.98 (H-2^- or H-3^-), 3.77 ( s, H-3^- or H-2^- ), 3.71–3.72 (H-4^- ), 3.62–3.629 (2H-5), 7.01-7.59 ( m, Aryl C-H), 3.79 ( s, O-CH₃).

4-(benzylideneamino) cytarabine (C7)

Molecular Formula: C₁₆H₁₇N₃O₅

Elemental Analysis: C, 58.00; H, 5.17; N, 12.68

Found: C, 57.899; N, 12.558; H, 5.001

m.p. 240-242 , yield 60%

IR (KBr disc, cm^-1): 3481, 3440 due to OH stretching, 3120 due to CH aromatic stretching, 2932, 2832 due to CH stretching, 1666 due to carbonyl group stretching,1638due to benzene ring stretching, 1580, 1531, 1483 due to C=N and C =C stretching, 1282, 1113, 1070 due to C-O stretching and 798 due to C-H bonding.

· ¹HNMR (Chemical shifts,δ, ppm)), (DMSO-d6) : 9.78( s, 1HC=N imine ), 7.659 (d , 1H-6, HC=N pyrimidine ring), 6.09 (d, 1H-1^-, anomeric), 5.72 (d, 1H-5, HC=N pyrimidine ring), 5.43–5.4(2^- OH or 3^-OH), 5.05 (5^-OH), 3.96 (H-2^- or H-3^-) , 3.76 ( s, H-3^- or H-2^- ), 3.71–3.72 (H-4^- ), 3.623–3.64 (2H-5), 6.95-7.399 ( m, Aryl C-H).

4-(2,4- dichlorobenzylideneamino) cytarabine (C8)

Molecular Formula: C₁₆H₁₅Cl₂N₃O₅

m.p. 240-242 , yield 60%

IR (KBr disc, cm^-1): 3482, 3447 due to OH stretching, 3144 due to CH aromatic stretching, 2949, 2876 due to CH stretching, 1660 due to carbonyl group stretching,1631 due to benzene ring stretching, 1581, 1529, 1480 due to C=N and C =C stretching, 1280, 1112, 1070 due to C-O stretching and 799 due to C-H bonding.

· ¹HNMR (Chemical shifts,δ, ppm)), (DMSO-d6): 9.73( s, 1HC=N imine ), 7.7( d , 1H-6, HC=N pyrimidine ring), 6.09 (d, 1H-1^-, anomeric), 5.72 (d, 1H-5, HC=N pyrimidine ring), 5.42–5.43(2^- OH or 3^-OH), 5.1 (5^-OH), 3.94 (H-2^- or H-3^-), 3.77 ( s, H-3^- or H-2^- ), 3.71–3.724 (H-4^- ), 3.6–3.71 (2H-5), 7.33-7.79 ( m, Aryl C-H).

4-(3-phenylallylidene)amino) cytarabine (C9)

Molecular Formula: C₁₈H₁₉N₃O₅

m.p. 240-242, yield 60%

IR (KBr disc, cm^-1): 3477, 3447 due to OH stretching, 3126 due to CH aromatic stretching, 2968, 2856 due to CH stretching, 1659 due to carbonyl group stretching,1628 due to benzene ring stretching, 1581, 1530, 1484 due to C=N and C =C stretching, 1280, 1114, 1070 due to C-O stretching and 798 due to C-H bonding.

· ¹HNMR (Chemical shifts,δ, ppm)), (DMSO-d6) : 9.71( s, 1HC=N imine ), 7.71( d , 1H-6, HC=N pyrimidine ring), 6.07 (d, 1H-1^-, anomeric), 5.71(d, 1H-5, HC=N pyrimidine ring), 5.436–5.447(2^- OH or 3^-OH), 5.07 (5^-OH), 3.94 (H-2^- or H-3^-) , 3.783 ( s, H-3^- or H-2^- ), 3.72–3.729 (H-4^- ), 3.63–3.60 (2H-5), 6.989-7.44 ( m, Aryl C-H),6.34(d, CH=CH-Aryl), 6.76(d, CH=CH-Aryl).

4-(4-chlorobenzylideneamino) cytarabine (C10)

Molecular Formula: C₁₆H₁₆ClN₃O₅

m.p. 240-242, yield 60%

IR (KBr disc, cm^-1): 3470, 3434 due to OH stretching, 3118 due to CH aromatic stretching, 2936, 2866 due to CH stretching, 1658 due to carbonyl group stretching, 1628 due to benzene ring stretching, 1578, 1529, 1480 due to C=N and C =C stretching, 1283, 1111, 1069 due to C-O stretching and 798 due to C-H bonding.

¹HNMR (Chemical shifts, δ, ppm)), (DMSO-d6): 9.69( s, 1HC=N imine ), 7.66( d, 1H-6, HC=N pyrimidine ring), 6.07 (d, 1H-1^-, anomeric), 5.71 (d, 1H-5, HC=N pyrimidine ring), 5.42–5.43(2^- OH or 3^-OH), 5.06 (5^-OH), 3.98 (H-2^- or H-3^-) , 3.75 ( s, H-3^- or H-2^- ), 3.71–3.72 (H-4^- ), 3.63–3.64 (2H-5), 7.21-7.49 ( m, Aryl C-H).

RESULTS AND DISCUSSION:

Cytarabine derivatives were designated and synthesis in the light of prodrugschiff base strategies. Cytarabine and aromatic aldehyde have been selected to their potential therapeutic advantages to produce cytarabine prodrug derivatives with predictable to improve the pharmacological action , reduce the adverse effects ,overcome drug resistance and explore new bio therapeutic criteria as anti bacterial action etc. The products identification by ¹H-NMR, FT-IR and (C.H.N.) microanalysis. The (C.H.N.) of some prepared compounds was accepted agreement with the calculated of elements percentage. Vibration spectroscopy (Theft infrared absorption spectrum) of cytarabine derivatives was obtained in a KBrdisk using a Shimadzu FTI.R spectrophotometer. The interpretation of the FT-IR spectrum confirms the principal peaks are observed at (3487- 3430 cm^-1) due to OH groups stretching of arabinose ring, (3120-3160 cm^-1) due to aromatic C-H stretching, (2970-2840 cm^-1) due to aliphatic C-H stretching, (1670-1656 cm^-1) due to carbonyl group stretching, (1588-1570 cm^-1) due to C=N stretching, (1549-1520 cm^-1) due to C =C stretching and (799-796 cm^-1) due to C-H bonding. (Assignment for the major infrared absorption bands are show above).The proton nuclear resonance (¹H NMR) spectra of cytarabine derivatives were obtained using a Bruker instrument operating at 400 MHz. The chemical shift consideration the doublets at near d 7.5 and 5.6 ppm are assigned for protons at positions 6 and 5 of the cytosine ring. Protons of aromatic ring of all synthesized compounds appear at 6.9-7.6 ppm. The distorted doublet at near d 7.09–7.1 ppm is assigned for the 4-amino function. Anomeric proton resonated at near d 6.04 ppm. Peaks of other protons (2^-, 3^-, 4^-and 5^-) are showed above data. The final compounds (cytarabine prodrug) new derivatives have been synthesis zed and confirmed by FTIR spectroscopy, (C.H.N) micro analysis and the proton nuclear resonance (¹H NMR) spectra and some important physiochemical properties.

Fig.1¹H-NMR Spectrum of (C2)

Fig.2¹H-NMR Spectrum of (C3)

Antibacterial activity test:

Cytarabine derivatives (C1-C6) were tested for antibacterial activity against some bacteria such as Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus in Muller Hinton agar method, by determine the inhibition zone in (mm). Each bacteria isolate was inoculated on to the Muller-Hinton Agar [sterilize in autoclave] by dipping a cotton swab in to the suspension and streaking over the surface of the agar plates. Then, in the solidified medium, holes were made (6 mm). These holes were filled with (0.5 ml) of the prepared compounds ((300 µg/ µL) of the compound dissolved in 1ml of DMSO solvent). These plates were incubated at 37 ⁰C and measured of zone inhibition after 48 hours. The results are presented in Table 1.

CONCLUSION:

In the present study, the new derivatives of cytarabine anti neoplastic agent have been designed and synthesized. They are considered one of an Schiff bases imine prodrug strategies to improve the pharmacological therapeutic dual utility of cytarabine as anti neoplastic and anti viral action and to export other potential therapeutic area and to overcome the major limitation of cytarabine drug resistance. The cytarabine new derivatives have marked anti bacterial action and can use it as searching nucleus for other therapeutic area.

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1. The American Society of Health-System Pharmacists. 8 December 2016.

2. Wilson and Griswold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry; Twelfth Edition; John M. Beale, Jr., PhD Associate Professor of Medicinal Chemistry 2011 by Lippincott Williams and Wilkins, a Wolters Kluwer business; pp340.

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Received on 12.12.2017 Modified on 05.01.2018

Research J. Pharm. and Tech. 2018; 11(3): 1131-1136.

DOI: 10.5958/0974-360X.2018.00211.1

CYTARBINE DERVITIVES	*E. coli*		*S.aureus*		*P. aeruginosa*
CYTARBINE DERVITIVES	Inhibition Zone(mm)	% Inhibition	Inhibition Zone(mm)	% Inhibition	Inhibition Zone(mm)	% Inhibition
C1	30	120	5	20	10	35
C2	26	85	35	145	18	65
C3	20	70	15	55	15	55
C4	10	35	0	0	14	55
C5	0	0	10	35	10	35
C6	10	35	22	78	30	120