Announcement about the defense of the doctoral (DSc) thesis of Zhurakulov Sherzod Niyatkobulovich

I. General information.

The topic of the dissertation, specialty code (the name of the branch where the academic degree is awarded): «Synthesis, modification and biological activity of tetrahydroisoquinoline, quinazolone alkaloids and their derivatives», 02.00.03 – Organic chemistry, 02.00.10 –Bioorganic chemistry (chemical sciences).

Dissertation topic registered number: B2023.2.DSc /K158.

Scientific advisors: Elmuradov Burkhon Jurayevich, doctor of chemical sciences, professor. Sagdullayev Shamansur Shakhsaidovich, doctor of technical sciences, professor.

Name of the institution where the dissertation was completed: Institute of the Chemistry of Plant Substances.

Name of the institution where the scientific council works, Number of the scientific council: Institute of the Chemistry of Plant Substances, DSc.02/30.01.2020.K/T.104.01.

Official opponents: Tashmukhamedov Mugrajitdin Salakhovich doctor of chemical sciences, professor; Kholikov Tursunali Suyunovich, doctor of chemical sciences, docent; Khodjaniyazov Khamid Utkirovich, doctor of chemical sciences, leading scientific researcher.

Leading organization: Samarkand State Universit

Dissertation direction: theoretical and practical.

II. The aim of the research work is development of optimal methods for the synthesis of new heterocyclic molecules in a number of isoquinoline and quinazolone alkaloids, carrying out their targeted chemical modifications, comparing the results obtained, determining the structures, physico-chemical and pharmacological properties of synthesized substances and identifying the relationship "structure-biological activity".

The scientific novelty of the dissertation research is as follows:

a systematic study was conducted on the directed synthesis and chemical modification of tetrahydroisoquinolines, tricyclic quinazolones and their derivatives, 134 new compounds were synthesized and their structure was proved by modern physical research methods;

it was found for the first time that the reaction of 3,4-dimethoxyphenyl-ethylamine with aromatic aldehydes, depending on the nature and type of substitution in the aromatic ring, the type and amount of acids and the temperature of the medium, proceeds with the formation of Schiff bases or target 1-aryl-6,7-dimethoxy-tetrahydroisoquinolines;

it was revealed that the interaction of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolines with alkyl bromides in various solvents proceeds chemoselectively with the formation of N-alkyl derivatives; at the same time, the most optimal condition is: the ratio of reagents is 1:2, DMF solvent, reaction time is 6-8 hours;

it was found that the reaction of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolines with allyl bromide, depending on the structure of the substrates, the ratio of reagents and the temperature of the reaction medium, proceeds with the formation of isomeric C-, N-, O-allyl derivatives with a high synthetic potential;

the synthesis of new methylene-bridged hybrid molecules by the three-component Mannich reaction of 1-aryltetrahydroisoquinolines with uracil and 6-methyluracil in the presence of formalin was carried out for the first time; the main factors influencing the type and yield of the final products were identified;

for the first time by the Mannich reaction 1-(H, methyl, aryl)tetrahydroisoquinolines with dihydroquercetin and quercetin were synthesized into new alkaloid-flavonoid bimolecular molecules and it was found that, depending on the structure of the substrates, the ratio of reagents and the order of addition, mono- and disubstituted products or annelated oxazine are formed;

it was found that the aminomethylation of quercetin with 1-aryl-1,2,3,4-tetrahydroisoquinolines, in contrast to the similar reaction with dihydroquercetin, proceeds exclusively with the formation of 8-monosubstituted hybrid molecules; which indicates the inactivity of the quercetin position 6 for electrophilic substitution;

it is proved that the nucleophilic substitution of 3-hydroxymethylidene-deoxyvasicinone and 4-formylmackinazolinone by primary amines proceeds with the formation of aminomethylidene-derivatives existing in Z- or (and) E-configurations, whereas secondary amines do not react with 4-formylmakinazolinone due to the existence of the latter in a stable enaminoaldehyde form, which has been proven experimentally and calculated methods;

it was found that the reduction of 4-formylmackinazolinone by sodium borohydride is selective for the aldehyde group and endocyclic double bond with the formation of 6-(hydroxymethyl)-5,5a,6,7,8,9-hexahydro-11H-pyrido[2,1-b]quinazoline-11-one, which as a result of dehydration and redox the reaction easily turns into a racemic mixture of hydroxymethyl and methyl derivatives of mackinazolinone;

the effect of acids on the aminomethylidene derivatives of tricyclic quinazolones was studied for the first time; in this case, instead of the expected bis-products "quinazolinone-isoquinoline", the exocyclic C=C cleavage occurs due to the formation of the alkaloids deoxyvasicinone and mackinazolinone, as well as the cyclization product of the aminomethylidene fragment to 3,4-dihydroisoquinoline;

By studying the relationship between the structure of compounds and their cytotoxic activity, it was revealed that the cytotoxic activity of 1-aryltetrahydroisoquinoline is manifested in the presence of two methoxyl groups in the A ring and the presence of a methylenedioxyphenyl fragment in the C-1 position, a halogen atom in the ortho position, which have cytotoxic activity against HeLa cells.

IV. Implementation of the research results. Based on the scientific and applied research results on the synthesis and chemical modification of tetrahydroisoquinolines and tricyclic quinazolones, their new derivatives, determination of the structures and pharmacological properties of the compounds obtained:

a patent for an invention (No. IAP05489, 2017) of the Intellectual Property Agency of the Republic of Uzbekistan for an atypical sedative-anxiolytic agent was obtained. As a result, a highly effective atypical sedative has been created with fewer side effects and greater pharmacological breadth for use in medicine;

a patent for an invention (No. IAP05766, 2019) of the Intellectual Property Agency of the Republic of Uzbekistan for a drug with selective cytotoxic activity was obtained. As a result, a substance was obtained that is recommended as an active compound for the creation of a new antitumor drug;

a patent for an invention (No. IAP06321, 2020) of the Intellectual Property Agency of the Republic of Uzbekistan for an atypical neuroleptic agent was obtained. As a result, a low-toxic compound was created with less inhibition of motor activity, as well as fewer side effects for use in medical practice;

a patent for an invention (No. IAP06625, 2021) of the Intellectual Property Agency of the Republic of Uzbekistan was obtained for a method for producing 1-(4-dimethylaminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride that exhibits local anesthetic, analgesic and antiarrhythmic effects. As a result, a low-toxic compound with a greater pharmacological breadth was created for use in medical practice;

a patent for an invention (No. IAP06753, 2022) of the Intellectual Property Agency of the Republic of Uzbekistan for a cardioprotective agent was obtained. As a result, an effective remedy for the treatment of coronary heart disease and heart failure is recommended;

the X-ray structural analysis data of 5 new compounds are included in the Cambridge central crystallographic database (The Cambridge Structural Database, https://www.ccdc.cam, CCDC 2049242, 2047824, 2004621, 2039173, 2039174). As a result, the new compounds introduced into the database are used in the synthesis and description of structures of similar heterocyclic substances;

materials on the synthesis and modification of derivatives of 1-aryl-1,2,3,4-tetrahydroisoquinolines and their analogues were used in foreign journals with a high impact factor (IF) for the synthesis of new derivatives, determination of their structures and in the physico-chemical analysis of compounds of this class (Current Bioactive Compounds, 2019, V. 15, P. 71-82, IF 1.045; Tetrahedron Letters, 2017, V. 58, P. 294-297, IF 2.081; Chemistry of Natural Compounds, 2017, V.53, P. 145-151, IF 0.85; Catalysts, 2020, V. 10, P. 2-11, IF 3.9; Chemical Papers, 2018, V. 72, P. 1399-1406, IF 2.159; Journal of Environmental Chemical Engineering, 2023, V.11, P. 109042, IF 7.968). The results allowed for the targeted synthesis, modification and identification of new hybrid products of tetrahydroisoquinolines and dihydroquercetin.

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