Хімія та хімічні технології/ 6. Органічна хімія

О. I. Panasenko, V. P. Buryak, A. S. Gotsulya, S. M. Kulіsh

Zaporozhye State Medical University

Basic optical characteristics of the electronic absorption spectrum (BOCEASP) of drugs. Determination BOCEASP of drugs, containing in the molecule non-condensed furan cycle

Development of pharmaceutical chemistry put on the next tasks in front of the molecular spectrophotometry: calculating of the electronic condition, prediction and explanation of different properties of complex polymolecular organic compounds. To solve these problems, the most commonly used method of ultraviolet spectrophotometry, which on the basis of the BOCEASP calculation can explain the electronic structure of studied compound and to determine the molecule fragment that determines the pharmacological activity of the molecule.

Keywords: pharmaceutical chemistry, molecular spectrophotometry, optical characteristics, UV spectra.

BOCEASP included in the State Pharmacopoeia of Ukraine [6] are the wavelengths λ_max (in nm) and specific absorption index - . At the same time for chemical reagents, dyes and other chemical compounds in the last 10 years have been widely used also other BOCEASP: wave number at the maximum of absorption - ν_max (cm^-1); bold absorption band Δv_1/2 (cm^-1); the integral intensity of the absorption band (in L-mol•cm²), the oscillator strength of the electronic transition - f; the transition matrix element - Mik [4, 5, 8, 9].

Introduction of the specified BOCEASP in a practice of pharmaceutical analysis is undoubtedly expedient, as these quantities may be used for drugs identification, similar in their chemical structure; for deep study of the molecules electronic structure, and also may be used as important parameters for communication establishment between the structure and pharmacological activity.

The purpose of work. In our work cycle we set the aim to study the OOHESP of twenty-nine drugs, containing in their molecule -O and -O, N-heterocycles, and also for several hormonal drugs comparison, characterized by very close in value quantities λ_max.

Materials and methods. All researched drugs, containing in a molecule non-condensed furan cycle, completely comply with the requirements of the State Pharmacopoeia, and their standard samples were obtained from the State Enterprise Scientific-Expert pharmacopoeia center of Ukraine. In all cases, as a solvent we used 95% ethyl alcohol.

UV-spectra of test compounds were measured by means of the spectrophotometer SPECORD 200-222U214 (Germany).

Results and their discussion. We have defined and calculated BOCEASP of UV-spectra of twelve drugs in ethanol, which are furan derivatives (furagine, furagine soluble, furazoline, furazolidonee, furadonine, furatsiline, nitrofurilene, furazonole, fubromegane, furasemide, larusane, ftorafure) and of two model compounds (uracile, 5-fluorouracil).

The absorption bands of all researched drugs with non-condensed furan cycle are interferential or high-intensity, as indicated by the molar absorption coefficient, the value of which ranges from 4500 to 34000 (the third and the first absorption bands of furosemide). It should be noted that for studying of 5-nitrofuran derivatives these quantities E_max are situated in more narrow ranges, namely from 8300 (first nitrofurilene band) to 25500 (the third furagine band). This indicates that all absorption bands may not correspond to π→π* transitions, which are characterized by low-intensive bands [7].

The half-width of the absorption band is broad (from 2970 to 9850 cm^-1) for twenty from the twenty-seven observed bands. Very broad, i. e. with Δν_1/2 = 10,000 cm^-1 and higher, is the first furagine band and its potassium salt, furazolidone, furadonine, nitrofuragine, and also first and second furazolidone bands (Table. 1).

Drugs, which are 5-nitrofurane derivatives, present relatively homogeneous group by quantities of the integral intensity of the A absorption bands. All these quantities are high and situated in the ranges from 0,87 ∙ 10⁸ to 1,49 10⁸, that indicates on a high probability of electrons transition, causing the appearance of absorption bands of nitrofurane derivatives. Exclusion is the second absorption band of furadonine, characterized by the average quantity of the integral intensity (A = 0,67 ∙ 10⁸).

It should be noted, however, that for the absorption band of 5-nitrofurane derivatives with λ_max in area 332-385 nm, quantities A are the highest. Namely this band arises as a result of coupling reaction in chromophores, containing in their structure the nitro group. Presence of these chromophores causes the antimicrobial activity of 5-nitrofurane derivatives that is why we can consider them as pharmacophores (or their part).

Drugs, containing in their molecules a furan cycle, but without a nitro group (fubromegane, furosemide, larusane, ftorafure) containing in UV-spectra four bands with high quantities of the integral intensity (from 0,89 ∙ 10⁸ to 1,88 ∙ 10⁸) and at the band with the average A quantities (from 0,22 ∙ 10⁸ to 0,63 ∙ 10⁸). Thus, the transitions of electrons, causing the appearance of these bands are probable or highly probable.

The lowest quantity A, namely 0,22 ∙ 10⁸ is observed for the middle band absorption band of furosemide with λ_max at 334 nm. Maximum relates to ¹L_b band, which cannot has any direct connection with the pharmacophore, which causes the diuretic effect of the drug.

Quantities of the oscillator force f for all absorption bands of 12 studied drugs with non-condensed furan cycle are situated in the ranges from 0,24 to 2,00 (Table. 1). Decimals logarithms of these quantities are from 0,62 to 0,30 at quantities ln ε_max, located in the ranges from 3,65 to 4,54. Thus, in accordance with the scale of the oscillator strengths of molecular electronic transitions, composed by Kashe Rawls [10], electron transitions, causing the appearance of the absorption bands of 5-nitrofurane, fubromegane, furosemide, and lorisane and ftorofure derivatives are permitted.

Found quantities of Mik matrix element transition are high and compose from 3,6 ∙ 10^-18 (second absorption band of the furosemide) to 6,46 ∙ 10^-18 (absorption band of the larusane). These quantities are not directly proportional to the reactionary ability, corresponding to the chromophore or pharmacophore, but in certain degree, indicate that these groups of atoms are highly reactive.

Table 1

Optical characteristics of the electronic absorption spectra of drugs, containing in their molecule non-condensed furan cycle

№ o\o	Drugs	Solution conc.	λ, nm.	��, сm^-1	10^4		��½	А10^8	f	Mik10^-18
1.	Furagine	1 mg % ethanole	245 292 380	40820 34250 26320	0,86 2,11 2,55	3,94 4,33 4,41	10720 6060 5460	0,99 1,37 1,49	1,07 1,46 1,59	4,30 5,50 6,54
2.	Dissolved furagine	1 mg % ethanole	232 292 385	43100 34250 25970	1,03 1,92 2,39	4,01 4,28 4,38	12120 5980 5770	1,34 1,23 1,48	1,43 1,31 1,58	4,85 5.21 6,56
3.	Furazole	1 mg % ethanole	234 265 356	42740 37740 28090	0,88 0,95 1,57	3,94 3,98 4,20	13460 10150 6180	1,27 0,98 1,04	1,35 1,05 1,11	4,70 4,44 5,34
4.	Furazolidone	1 mg % ethanole	234 265 356	42740 37740 28090	0,88 0,95 1,57	3,94 3,98 4,20	13460 10150 6180	1,27 0,98 1,04	1,35 1,05 1,11	4,70 4,44 5,34
5.	Furadonine	1 mg % ethanole	225 272 356	44440 36760 28090	0,85 0,85 1,30	3,96 3,96 4,15	10000 7380 6370	0,91 0,67 0,87	0,97 0,72 0,93	3,92 3,70 4,62
6.	Furaciline	1 mg % ethanol	263 364	38020 27470	1,17 1,82	4,07 4,26	9850 5360	1,13 1,05	1,21 1,13	4,74 5,40
7.	Nitrofurilene	1 mg % ethanol	244 347	40980 28820	0,83 1,97	3,92 4,30	10000 5270	0,89 1,11	0,95 1,19	4,05 5,41
8.	Furazonale	1 mg % ethanole	239 332	41840 30120	1,12 1,99	4,05 4,30	7620 5430	0,91 1,16	0,98 1,23	4,10 5,39
9.	Fubromegane	1 mg % ethanole	220 265	45450 37740	1,68 1,72	4,23 4,24	5680 4810	1,02 0,89	1,10 0,95	4,10 4,22
10.	Furocemide	1 mg % ethanole	230 274 334	43880 36500 29940	3,44 1,99 0,45	4,54 4,30 3,65	5110 2970 4540	1,88 0,63 0,22	2,00 0,67 0,24	5,71 3,61 2,39
11.	Larusane	1 mg % ethanole	334	29940	2,96	4,47	5190	1,64	1,76	6,46
12.	Furacile	1 mg % ethanole	258	38750	0,79	3,90	4870	0,42	0,48	3,00
13.	5-Furfurole	1 mg % ethanole	267	37450	0,69	3,84	5060	0,37	0,40	2,70
14.	Ftorafure	1 mg % ethanole	270	37050	0,85	3,43	4710	0,43	0,45	3,00

For a more completely interpretation of ftorofurane UV-spectra were determined uracil and 5-fluorouracil BOCEASP in ethanol solutions for a comparison of these compounds as models. In addition, we calculated these characteristics also for cyclohexane solution of ftorfurane.

During the transition from non-polar solvent (cyclohexane) to polar (ethanol) absorption maximum, and also the integral intensity of the A absorption band, the oscillator strength of the electronic transition f and the transition matrix element Mik are almost unchanged within the limits of experimental errors. This proves that the band at 270 nm corresponds to electrons transfer of the chromophore, not π→π* local excitation of the nucleus.

Similar quantities A, f and Mik for uracil (1), 5-fluorouracil (2) and ftorfurane (3) are evidence that all of these compounds are characterized by a one chromophore, namely:

Introduction of the electron-donor F atom at C⁵ promotes to the electrons transfer, resulting in a bathochromic displacement of maximum on + 9 nm or ≈ 3,7 kkal/mol. Simultaneously, a fluorine atom violates the complementary of a molecule, as a result is observed a decrease of the extraction in 1.4 times. The band at ≈270 nm cannot correspond to the chromophore:

This chromophore is contained in the tautomeric form of ftorafurane (4), because in this case the fluorine atom would not affect the position of the absorption maximum.

Further substitution of H atom at the N¹ atom in a molecule (2) on the tetrahydrofurane residue, only in a small degree promotes to the transfer of electrons in the chromophore.

High quantities of the oscillator strength (0,40-0,48), expressed as the ratio of the average value of the oscillating charge in the molecule to the charge of a single electron, indicates not only on the allowed transition, also on high probability of electron transfer in the chromophore. Thus, uracil in ethanole solution exists in a form 1,2,3,4-tetragidropirimidindiol-2,4, instead of 2,4-dioksipirimidine.

Based on the identity of spectrums (4) in etalon and aqueous solutions we can suggest that (4) is not exposed dissociation to the ions in the water, in alkaline solutions is observed at 220-240 nm a very strong increase of the extraction, indicating on a salt formation of type (5). As is well known, the maximum, corresponds to the electrons transfer in the amide chromophore -NC=O, is situated below 200 nm [8]. This electrons transfer will be greatly increase at the ions formation of (5) form with the negatively charged nitrogen atom. About the formation of similar mono-anions informs R. A. Juyk and coauthors [1].

Pic. 1. Structure of the researched compounds

On the basis of presented facts we can judge that the physiologically active moiety contained in the molecules of fluorouracil and ftorafure is a pharmacophore [3].

Conclusions

1. Established that Δλ_1/2 and the integral intensity of the absorption bands A, the oscillator strength f and Mik matrix element transition can serve as important constants of drugs for their identification and the establishment of deeper connection between spectrums and the structure of the molecule.

2. For drugs, 5-nitrofurane derivatives, the most characteristic is the third absorption band with very high values A and f; for specified compounds chromophores and pharmacophores apparently coincide.

3. All electrons transitions, causing the appearance of the absorption bands of drugs, containing in the molecule O-heterocycles are permitted and in most cases, have a high probability.

4. On the basis of OOHESP studying possible we can claim that the pharmacophore in a molecule of 5-fluorouracil and ftorafure is a group:.

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