Design, synthesis, and biological evaluation of some new charge transfer complexes as a combination model

The present work includes design and synthesis a new model of charge transfer complexes from simvastatine which is antihyperlipidemic drug as acceptor with angiotensin receptor blockers(candesartan ,losartan ,valsartan ,telmis-artan ,irbesartan) as donors and characterization the models by UV, FT-IR ,HNMR spectrophotometry , it shows change in spectral peaks which refer to formation of charge transfer complexes. And study the effect of interaction on availability of drugs with the time , different PH and different concentrations. Which shows the variability in availability of drugs in combination (charge transfer complexes) due to PH , concentration, and time changing, this variability in availability mostly effect on simvastatine which mean decrease or absence the availability of simvastatine and increase the availability of angiotensin receptor blockers ( mostly not absolutly). Beside this we study the evaluation of biological activity of combinations and compare with the biological activity of simvastatine alone on the lipid pro(cid:977)ile of rabbits , by induced hypercholesterolemia in rabbits for two weeks (except the positive control group) and gave the drugs for four weeks and measuring the lipid pro(cid:977)ile changing in order to improve the change in the ef(cid:977)icacy of sim-vastaine alone and simvastatine in combinations and this variability due to donor-acceptor interaction (charge transfer interaction)

charge transfer complex, simvastatine, angiotensin receptor blockers, UV spectroscopy, lipid pro ile ABSTRACT The present work includes design and synthesis a new model of charge transfer complexes from simvastatine which is antihyperlipidemic drug as acceptor with angiotensin receptor blockers(candesartan ,losartan ,valsartan ,telmisartan ,irbesartan) as donors and characterization the models by UV, FT-IR ,HNMR spectrophotometry , it shows change in spectral peaks which refer to formation of charge transfer complexes. And study the effect of interaction on availability of drugs with the time , different PH and different concentrations. Which shows the variability in availability of drugs in combination (charge transfer complexes) due to PH , concentration, and time changing, this variability in availability mostly effect on simvastatine which mean decrease or absence the availability of simvastatine and increase the availability of angiotensin receptor blockers ( mostly not absolutly). Beside this we study the evaluation of biological activity of combinations and compare with the biological activity of simvastatine alone on the lipid pro ile of rabbits , by induced hypercholesterolemia in rabbits for two weeks (except the positive control group) and gave the drugs for four weeks and measuring the lipid pro ile changing in order to improve the change in the ef icacy of simvastaine alone and simvastatine in combinations and this variability due to donor-acceptor interaction (charge transfer interaction)

INTRODUCTION
The term charge transfer complex (CTC) was irst used by Mulliken. He describes a new type of adduct to describe the behavior of certain molecular groups, which do not adhere to the traditional patterns of ionic, covalent, and hydrogen bonding components. While these adducts generally retain some of the component properties, some changes are obvious For example, its solubility, its diamagnetic and paramagnetic susceptibility. Charging interactions within a molecular complex consisting of an electron donor D and an electron acceptor A include resonance with charging transfer from D to A (Abdulredha, 2015).
It is important phenomenon in the process of biochemical and bioelectrochemical energy. The term charge transfer gives kind of complex resulting from donor and acceptor interactions with the formation of weak bonds and widely discussed by Foster. In molecular interactions between electron donors and receivers are correlated with formation of strongly colored charge Transfer complexes (CTCs) which absorb radiation in visible region. Important processes in biological systems are molecular complexation and structural recognition. Drug action, catalysis of enzymes and movement of ions via lipophilic membranes all require complexation.

Figure 1: Chemical structures of (a) simvastatine (b) candesartn (c)valsartan (d) irbesartan (e) telmisartan (f) losartan
The key directors of the speci icity, rate regulation and reversibility are the characteristics in many biochemical reactions (Arslan and Duymus, 2007) . Many drugs are easily identi iable by spectrophotometry on the basis of complex color transfer charges formed between electron acceptors and electron donors. Methods of analyzing many drugs are recorded mainly by direct UV spectrophotometry, luorometry, polarography, colorimetry and HPLC (Duymus et al., 2006).The charging-transfer (CT) reaction between electrondonating and electron-accepting molecules is of considerable importance in various ields of chemistry due to their existence in biological systems, widespread applications as organic electrical conductors, the study of drug-receptor interaction mechanisms, the storage of solar energy and the study of thermodynamics and pharmacodynamics In medical molecules. CT reactions are generally associated with the development of strongly colored CT complexes, which normally absorb radiation; however, a new light-absorbing band exists at much longer wavelengths than in the CT complex component spectrum. The rapid creation of these complexes results in their comprehensive usefulness in the production of spectrophotometric methods for analyzing many organic and/or pharmaceutical molecules (Darwish et al., 2014),spectrophotometric assays offer signi icant economic advantages over gas chromatography and high-performance liquid chromatographic techniques (Shahdousti et al., 2008) . Obtain quantitative estimates of drugs in pure form or in cheaper, faster, quicker and more precise pharmaceutical preparations . Plays important roles in many biological ields such as DNAbinding, antibacterial, antifungal and insecticidal Some CT drug complexes exhibit antimicrobial activity against gram-positive and gram-negative bacteria and fungi (Adam, 2014) Chemistry of CT or Hbonding interactions between either drugs or biological compounds and small organic or inorganic solid-state molecular acceptors In recent years, the solution has attracted growing attention, considerable interest and increasing signi icance and  (Roy et al., 2006), vitamin K with quinine and quinidine (Dozal et al., 2000) , losartan with iodine (Darwish, 2005) , losartan with antidiabetic (Mirza et al., 2013) ,determination of dapson by charge transfer complex formation with chloranil (Al-Ennizi et al., 2020), complex formation with metals (Nawar et al., 2020) .

Objective of the work
1. Synthesis a complex model from combination of two drugs by a charge transfer complex formation.
2. Study the effect of solvents on complex.
3. Study the effect of time on complex.
4. Study the effect of temperature and PH on complex.
5. Evaluation the bioavailability of each drug in complex. 2. valsartan, sigma -aldrich Germany.
6. simvastatine, sigma -aldrich Germany.  Figure 1) each of these sartans in 40 ml of methanol separately. The solutions have been mixed (each donor has an acceptor) with regular stirring and re lux in a round bottom lask. TLC had monitored and tracked the progress of the reaction. Solvent was evaporated after the reaction was completed. Re-crystallization of the compounds in methanol puri ied the products: chloroform (8:2) (Arayne et al., 2009) . The products of reaction seen in Table 1 , Figures 2  and 22.

FT.IR spectrum
Infrared spectra of the synthesized compounds..were recorded by .FT-IR. 8400S Shimadzu. spectrophotometer (Japan) using KBrdisk in range 4000-400 cm −1 at Department of pharmaceutical chemistry /collage of pharmacy /university of Basra.

Complex 1
Show strong broad at 3475 cm −1 refer to O-H ,at 3444 cm −1 attributed N-H, strong band

Complex 4
Show strong broad at 3383cm −1 refer to O-H ,
As a result of all complexes peaks ; there is a broad OH band, shift C=O band of carbonyl to the right ,decrease the intensity of C=C , C-O, and C-N bands.

H-NMR Spectra
The compounds were studied for 1 H-NMR Spectra at the analytical Laboratory of Tehran University, College of Sciences, Chemistry Department, using 500MHz NMR (INOVA Switzerland). DMSO-d 6 was used as a solvent and TMS as an internal standard. As a consequence of all HNMR complex peaks Most peaks are moved to the right (shielding).

Study the effect of solvents on charge transfer complexes
Dissolve 1* 10-5 molar concentrations of each complex (1 to 5) in 10 ml of each solvent (acetone, dichloromethane, chloroform, methanol, ethanol, dmso) and watch the effect by UV spectroscopy. The Study shows that the use of ethanol and methanol as solvents is ideally suited to stability of complexes.

Study the effect of time on charge transfer complexes
Dissolve 1* 10 −5 molar concentration of each complex (1 to 5 ) and determine the effect by UVspectroscopy within 5 to 30 min ,with 5 min as interval. As seen in Figures 3, 4, 5, 6 and 7 and this is mostly referred to raise the concentration of complexes after 5 min of addition or mixing .

Study the effect of concentration on charge transfer complexes
Various concentrations of complexes versus absorbance. As in Figures 8, 9, 10, 11 and 12 and this to improve the concentration is located with the linearity which is 1* 10 −5 according to beer ′ s law (Ibezim, 2012).

Study of interaction
Using Caleva dissolution tester at Department of pharmaceutical /collage of pharmacy /university of Basrah. simvastatin interaction with sartan was performed in vitro in the same set of dissolution media. Simvastatin was added to the dissolution medium already established at 37 • C at zero time in each set of experiments, while sartan was added after 15 minutes of time interval. aliquots were removed and assayed. Absorbance of each drug versus time In each experiment set was determined (Arayne et al., 2006). As in Figures 13, 14 , 15, 16, 17, 18, 19, 20 and 21 and from this study we see the availability of sartan increase mostly while availability of simvastatine decrease or absent at PH 1,4, 7.4 and 9. .( availability of simvastatine in complex 4 is zero ). So the effect of PH on complexes is various due to acidity and basicity

Biological activity
Using 24 white rabbits (male) (weight 1.5 to 2 kg) divided into 8 groups each one includes 3 rabbits ive group for ive complexes and one negative control and one for positive control and one for simvastatine alone ,induce hypercholesterolemia for two week to all groups (except the positive control group). After this period the drug model was given to each category as a classi ication for four weeks, then the lipid pro ile (cholesterol, triglyceride, LDL, HDL) was calculated and the difference in availability was found between the complex and simvastatin alone (Mohammadi et al., 2009;Mehta et al., 2003;Cavallini et al., 2009)as seen in Table 2.
Abbreviations For Table 2

CONCLUSIONS
Charge transfer complexes (1,2,3,4 and 5) characterized by the UV, IR, HNMR spectrophotometry studies . The effect of CT interactions that decrease or increase the availability of acceptor or donor and this depends mostly on temperature and PH. In this study, the availability of simvastatin (acceptor) is shown to be decreased or absent and increased for donors (1,2,3,4 and 5). Dose adjustment for both drugs (acceptor and donor) is required if both drugs are given at the same time or in conjunction with two drugs. The biological activity of the combinations is not clear because the sample is small (three rabbits in each group) and a large sample (at least 10 rabbits in each group) is required for further studies. To get a good picture of the difference between combinations and simvastatin alone for the effect on the lipid pro ile.

ACKNOWLEDGEMENT
I would like to thank collage of pharmacy /university of Basrah /pharmaceutical chemistry department , pharmaceutics department for providing laboratory facility for this work and veterinary Dr. Khaled Mezhir and clinical chemist Mohsen Enad for helping me in biological activity test ( in rabbits ) and lipid pro ile measuring.

Funding Support
Nil.

Con lict of Interest
Nil.