Pharmaceutical Chemistry Journal (v.50, #6)

The role of the antioxidant properties of 2,3,5,6,8-pentahydroxy-7-ethyl-1,4-naphthoquinone in the manifestation of its pharmacological effects is reviewed. Issues with pleiotropic cellular-molecular mechanisms of echinochrome A action are considered with emphasis on the unique antioxidant activity of 2,3,5,6,8-pentahydroxy-7-ethyl-1,4-naphthoquinone. These properties in combination with a low destructive potential account for the prospects of expanding the therapeutic use of echinochrome A.
Keywords: polyphenols; antioxidants; echinochrome A

Synthesis and Antidepressant Properties of 2-[3-Methyl-7-(Thietanyl-3)-1-Ethylxanthinyl-8-Thio] Acetic Acid Hydrazides by L. A. Valeeva; G. G. Davlyatova; Yu. V. Shabalina; A. V. Isakova; F. A. Khaliullin; I. L. Nikitina (358-361).
2-[3-Methyl-7-(thietanyl-3)-1-ethylxanthinyl-8-thio]acetic acid hydrazide was synthesized in two steps by our improved method. The structures of the synthesized compounds were confirmed by IR and NMR spectroscopic data. The acute toxicity was studied. The LD50 values were 700 mg/kg for outbred albino mice. Tail-suspension tests (TST) and forced swimming tests (FST) found that 2-[3-methyl-7-(thietanyl-3)-1-ethylxanthinyl-8-thio]acetic acid hydrazide exhibited antidepressant activity that was most pronounced at a dose of 12 mg/kg.
Keywords: xanthines; thietanes; hydrazides; acute toxicity; antidepressant effect; mice

Synthesis and Immunotropic Activity of Quinazolin-4(3H)-One Carbonyl Derivatives by M. A. Samotrueva; A. A. Tsibizova; A. A. Ozerov; S. A. Luzhnova; E. G. Glukhova; I. N. Tyurenkov (362-364).
Novel benzannelated pyrimidines, i.e., quinazolin-4(3H)-one derivatives, were synthesized and studied experimentally for possible immunotropic properties. Immunocorrection properties were observed for some substances (VMA-13, Nos. 01-04) with respect to immunosuppression caused by cyclophosphamide.
Keywords: pyrimidine compounds; quinazoline derivatives; immunocorrection; cyclophosphamide; synthesis

Guided by bioisosteric replacement principles, a series of new N-(hetarylmethyl)-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxamides were synthesized. Pharmacological tests showed that replacement of the benzyl phenyl ring in N-benzyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxamides by an isosteric heterocycle led to a noticeable increase in the analgesic activity only for the 3-Py derivative. The corresponding isomeric 2- and 4-Py derivatives were close to the benzylamide baseline level of analgesic properties whereas the furan, tetrahydrofuran, and thiophene analogs were characterized by a significant decrease in the analgesic activity.
Keywords: 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides; synthesis; amidation; analgesic activity; bioisosteric replacements

Synthesis of New Acetaminophen Analogs and Their Ibuprofen Conjugates as Novel Analgesic Drugs by Abbas Ahmadi; Mohsen Khalili; Samira Sadeghi; Neda Soleimani; Babak Nahri-Niknafs (369-376).
In this research, new analogs of acetaminophen (paracetamol, I) with dimethyl and ethyl substitutions on phenyl moiety and sulfonamide modified by inserting alkylpiperazine derivatives were synthesized (II – V). Then, their conjugated compounds with ibuprofen were also synthesized (VI – IX) and the analgesic and anti-inflammatory activities of new drugs (II – IX) were evaluated in formalin tests on rats. Results indicated that the best analgesic activity was observed for compounds II and VI in diminishing chronic and VI – IX in acute thermal pain tests; in addition, compound VIII showed the best activity in diminishing inflammation. It was concluded that chemical structural binding of the potent synthesized drugs (II – V) with ibuprofen produced new superior antinociceptive and anti-inflammatory drugs (VI – IX) which could alleviate both pain and inflammation.
Keywords: paracetamol; sulfonamide-alkylpiperazine analogs; ibuprofen; analgesic and anti-inflammatory activities

Synthesis, Structural Characterization and Cancer Cell Cytotoxic Activity of Vadimezan Hydrazones by Shi-Jie Zhang; Feng Xu; Qiu-Fu Ge; Hai-Bo Li; Wei-Xiao Hu (377-381).
New vadimezan hydrazones were synthesized as E/Z isomers and characterized by IR, 1H NMR, MS, and HRMS techniques; the ratio of isomers was analyzed by NOESY spectra. All compounds were evaluated for their cytotoxic activities against endometrial Ishikawa, lung A549 and NCI-460, chorion Bewo, cervical HeLa and Siha, breast MCF-7, leukemia HL-60, liver BEL-7402, and stomach BGC-823 cancer cell lines in vitro by standard MTT assay. The preliminary pharmacological results indicated that compound 5c exhibited most promising cytotoxic activity against NCI-460 cell line with IC50 value of 7.01 ± 0.53 μM.
Keywords: vadimezan; hydrazine; synthesis; cytotoxic activity

Synthesis and Pharmacological Properties of 1,3-Bis[(S)Phenylethyl]Imidazolidine-2-Thione by Muhammad Naveed Umar; Mohammad Shoaib; Mohammad Sadiq; Muhammad Ayaz; Sumaira Miskeen; Ismail Shah; Imran Khan; Haroon Ur Rahid; Ikram Ilahi; Sher Wali Khan (382-387).
Enantiomerically and diastereomerically pure thiourea derivative (compound I) has been synthesized in two steps starting from (S)-1-phenylethanamine and 1,2-dibromoethane. Compound I was screened for various biochemical parameters including blood glucose level, serum total cholesterol level, serum bilirubin and triglyceride levels, serum glutamate pyruvate transaminase (SGPT) and alkaline phosphatase (ALP) activity in New Zealand White (NZW) rabbits. Compound I was also screened for brine shrimp cytotoxicity, antileishmanial and antioxidant activity. Acute toxicity tests in NZW rabbits were performed and the results showed that compound I was safe up to 2 mg/mL/kg rabbit body weight. For the blood parameters, it was found that compound I caused slightly reduced blood glucose level, increased blood serum bilirubin, ALP and SGPT levels, and caused no changes in cholesterol and triglyceride levels. Thus, results show that compound I possesses good cytotoxic, poor antileishmanial activity, and no prominent antioxidant activity.
Keywords: antileishmanial activity; antioxidant; brine shrimp cytotoxicity; blood parameters; cytotoxicity; thiourea derivative

Pharmaceuticals for Binary Radiotherapy and Their Use for Treatment of Malignancies (A Review) by V. N. Kulakov; A. A. Lipengol’ts; E. Yu. Grigor’eva; N. L. Shimanovskii (388-393).
Binary radiotherapy (BRT) is a type of radiation therapy that employs special drugs to direct ionizing radiation to a target. As a rule, the drug has no significant biological activity of its own. BRT causes damage due to interaction of secondary ionizing radiation with biological tissues. The special drug that accumulates selectively in a tumor contains chemical elements that absorb external ionizing radiation considerably more efficiently than the chemical elements in living tissues. The absorbed dose can increase from several percent up to five times as a result of the selective interaction of the external radiation with such drugs in tumors. Currently, two types of BRT exist, i.e., neutron-capture therapy (NCT), which uses neutron beams, and photo-capture therapy (PCT), which uses x-rays. NCT potentially has greater therapeutic efficacy than PCT. However, PCT equipment is less expensive and can be housed in existing clinical establishments. Numerous studies of BRT efficacy from many countries of the world indicate that this technology is potentially efficacious for treating malignancies. Introduction of BRT into clinical practice would enhance considerably the antitumor efficacy of radiotherapy and decrease the number of irradiations to a single one. The capability of BRT can be fully unleashed only by developing specialized drugs that satisfy the BRT requirements.
Keywords: photon-capture therapy; neutron-capture therapy; absorbed dose enhancement; pharmaceuticals; x-rays

Comparative Bioavailability of Tizanidine in Three Dosage Forms (6-MG Delayed-Release Tablets, Sirdalud Preparation, and 2-MG Tablets) by V. G. Kukes; D. V. Reikhart; V. S. Artnautov; E. V. Torshina; A. V. Kapashin; A. V. Belostotskii (394-403).
Valenta Pharm Co. compared the pharmacokinetic parameters in healthy volunteers of three prototype tizanidine dosage forms (delayed-release 6-mg tablets) and the reference drug sirdalud (2-mg tablets for a total dose of 6 mg, three tablets). This allowed the relative bioavailability of the three prototype tizanidine forms relative to sirdalud to be assessed. All three prototypes showed signs of delay based on MRT parameters of (2.217 ± 0.441) h for the sirdalud instant-release form and (6.529 ± 1.990), (5.951 ± 1.295), and (6.384 ± 2.339) h for prototypes T1, T2, and T3, respectively. High relative exposure levels of prototypes T1, T2, and T3 [AUC 103.80% (73.69 – 146.20), 124.14% (88.14 – 174.86), and 131.93% (93.66 – 185.82), respectively] with a significant decrease of C max (to 35.83, 38.78, and 40.79%, respectively) were demonstrated by analyzing the comparative bioavailability. A model pharmacokinetic study of the forms produced secondary modeling parameters that were similar to those obtained by an off-model method (89.19 – 122.71%). This confirmed that the developed model was acceptable for planning future clinical tests of these drugs.
Keywords: tizanidine; AUC ; C max

Four-Step Synthesis of Abiraterone Acetate from Dehydroepiandrosterone by A. N. Balaev; A. V. Gromyko; V. E. Fedorov (404-406).
A four-step synthesis of abiraterone acetate in good yield was developed. The synthesis employed Suzuki cross-coupling in the key step and produced the target compound in 99.8% purity.
Keywords: abiraterone acetate; manufacturing; androgen biosynthesis inhibitor

Use of Proteins to Increase the Aqueous Solubility of Rifapentine by K. P. Ostrovskii; N. S. Osipova; L. V. Vanchugova; E. V. Shipulo; É. R. Pereverzeva; I. D. Treshchalin; O. O. Maksimenko; S. É. Gel’perina (407-412).
Parenteral formulations of the poorly soluble antituberculosis antibiotic rifapentine were developed. Proteins (human serum albumin, succinylated gelatin, and sodium caseinate) were used to produce water-soluble forms of rifapentine by precipitation or homogenization. Ultrasonic homogenization gave the best results, i.e., stable colloidal suspensions with 9 – 10 mg of rifapentine per mL (practically 100 times greater than its water solubility). Dilution of the suspensions led to dissociation of the aggregates formed during the solubilization and formation of a clear solution. The particle size decreased to 10 – 20 nm, which corresponded to the particle size in a solution of the proteins at the same concentration. This would not cause embolization upon infusion of such water-soluble forms of rifapentine. The results indicated that the selected approach was promising for designing parenteral formulations of rifapentine.
Keywords: proteins; complexation; rifapentine; solubilization; tuberculosis

Issues Related to Patent Protecton of Darunavir and its Analogs by M. S. Goizman; O. A. Zotova; A. A. Kamalova; A. O. Popova; D. L. Shobolov; A. A. Korlyukov; K. Yu. Suponitskii; N. L. Shimanovskii; S. A. Zaitsev; E. V. Degterev (413-418).
It is shown that prolongation of patent protection for the antiviral drug darunavir by patenting it again as darunavir ethanolate is illegal. The claims of the successor patent “Pseudopolymorphic forms of a HIV protease inhibitor,” WO 2003106461 A2, are analyzed and shown to be invalid from both scientific and ethical viewpoints. It is established that darunavir was initially used as its ethanolate. Darunavir is one of the best protease inhibitors of both types of HIV. Currently, not only darunavir ethanolate but also amorphous darunavir (unsolvated) are used as active pharmaceutical ingredients with INN darunavir. This was confirmed by x-ray diffraction studies. Justification for the orderly invalidation of this patent in the RF was given.
Keywords: inhibitor; protease; HIV; antiviral drugs; patent; drug safety; pseudopolymorph; drug substance; darunavir; ethanolate; amorphous; x-ray diffraction studies; patent claims; solvation; crystalline form

Rapid HPLC-MS/MS Determination of Carbamazepine and Carbamazepine-10,11-Epoxide by T. A. Rodina; E. S. Mel’nikov; A. V. Sokolov; A. B. Prokof’ev; V. V. Arkhipov; A. A. Aksenov; D. L. Pozdnyakov (419-423).
A rapid HPLC-MS/MS method for simultaneous determination of carbamazepine and carbamazepine- 10,11-epoxide in human blood serum was developed. The analytical range for carbamazepine was 50 – 20,000 ng/mL; for carbamazepine-10,11-epoxide, 5 – 2,000 ng/mL. This allowed the developed method to be used for therapeutic drug monitoring, bioequivalence studies, and an assessment of the interchangeability of carbamazepine preparations.
Keywords: carbamazepine; carbamazepine-10,11-epoxide; therapeutic drug monitoring; bioequivalence; interchangeability; HPLC-MS/MS