Vol 50, No 6 (2016)

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.

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.

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.

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.

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.

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.

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.

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.

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.