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HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Design, Synthesis and Antiviral Evaluation of Thiadiazole and Isothiazolone Derivatives

Author: WangSongQi
Tutor: LiuXinYong
School: Shandong University
Course: Medicinal Chemistry
Keywords: AIDS HIV-1 reverse transcriptase Non- nucleoside reverse transcriptase inhibitors 1,3,4 - thiadiazole Isothiazolone Synthesis Biological activity
CLC: R96
Type: Master's thesis
Year: 2008
Downloads: 87
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Abstract

Acquired immune deficiency syndrome, i.e. AIDS (Acquried the immunodeficiency or syndromeAIDS), is caused by the human immunodeficiency virus (Human immunodeficiency virus HIV) infectious disease. HIV is a retrovirus, is divided into HIV-1 and HIV-2 are two types. HIV-1 reverse transcriptase (reverse transcriptase RT) play an important role in the viral life cycle. Virus by reverse transcriptase single-stranded RNA reverse a double-stranded DNA, viral DNA then quickly integrated into the host DNA, the completion of the entire life cycle of the transcription, translation, and other. The unique features of reverse transcriptase in the virus life cycle makes it an important target for anti-viral treatment. Reverse transcriptase inhibitors are divided into two categories: nucleoside and non-nucleoside reverse transcriptase inhibitor. Nucleoside reverse transcriptase inhibitors (Nucleoside reverse transcriptase inhibitors NRTI) and substrate similar structure, competitively binding to the reverse transcriptase, inhibit the enzyme activity by blocking viral DNA chain extension; non-nucleoside reverse transcriptase inhibitors (Non-nucleoside reverse transcriptase inhibitors NNRTI) is a noncompetitive inhibitor of the reverse transcriptase, through the region in the vicinity of the sites of action of the action of the enzyme substrate with the RT deoxynucleoside triphosphates noncompetitive combine to change the role of the conformation of the sites to inhibit the enzyme activity. DAPY compounds recently discovered a class with high activity against HIV-1 non-nucleoside reverse transcriptase inhibitors. Not only does it inhibit nucleoside drug-resistant virus strains, variation and some other non-nucleoside reverse transcriptase inhibitors and drug-resistant strain of the virus is also inhibited. In order to get the higher of activity and selectivity of the variant virus strains inhibited but also with new structural skeleton NNRTI. Study DAPY class NNRTI lead compound, on the basis of a comprehensive study of structure-activity relationships, and learn from the diaryl the amines Thiazolidone class NNRTI's structural characteristics and binding mode bioisosteric principle, Flatten principle classical drug design methods to construct the 5 - aryl-methylene-2 ??- arylamino -1,3,4 - thiadiazole oxazole and 2 - substituted benzyl-4-cyano-5 - arylamino isothiazolones a new structural skeleton of the new NNRTI. The introduction of different substituents to build a structurally diverse compound libraries, and its virtual screening by using the Flex X module the Syble 7.0 software, docking score level, comprehensive evaluation, the structure of the target compounds. Technical novelty of the method in the field of drug design, innovative, reduce synthesis blindness, has a high value in use. Synthesis reaction urine aryl acetic acid with an amino sulfur as raw material by cyclization, diazotisation, Sandmeyer reaction, and finally through the aromatic amine the bromides nucleophilic substituted Preparation of 5 - methyl-2 - aryl, aryl alkylene amine yl-1 ,3,4 - thiadiazole compounds. Different isothiocyanate substituted with the different N-benzyl-2-cyanoacetamide electrophilic addition, the synthesis of a series of isothiazolones compound after bromine oxidation. Experiment two series of 38 new structures of compounds were synthesized, and the structure of the synthesized compounds by IR, MS. ^{1 H-NMR, ^{13 C-NMR and other spectral analysis confirmation. The compound synthesized in vitro anti-HIV-1 (IIIB) HIV-2 (ROD) activity screening. The test results show that: Part 5 - methylene-2 ??- arylamino, aryl-1 ,3,4 - thiadiazole compounds showed some HIV-1 activity, wherein the compound 5A5 of HIV-1 the EC _{of 50} of 54.0μM; compound is not HIV-2 (ROD) inhibitory activity. The preliminary structure-activity relationship analysis showed that the aromatic ring and the position of substituents play an important role in its anti-HIV-1 activity. In short, the paper DAPY class NNRTI lead compounds, and to learn from other structural features and has better high activity NNRTI binding mode, to build a new structural skeleton of the new NNRTI-5-aryl-methylene-2 ??- arylamino -1,3,4 - thiadiazole and 2 - substituted benzyl-4-cyano-5 - arylamino isothiazolyl trazodone. On the choice of the substituents, the use of computer aided drug design of compounds for virtual evaluation of scoring, the selective synthesis of the two series, a total of 38 new compounds. Synthesis: Research N replace isothiazolones step synthesis of compounds made useful exploration for future research; selective compounds 5a8 and 5a9 alkylation of the phenolic hydroxyl groups, has important practical significance. By 5 - arylmethylene -2 aromatic amine-1, 3,4 - thiadiazole compounds designed and synthesized by the anti-HIV-1 activity screening, found a new ring system, the structure of the HIV-1 inhibition agent of the lead compound, and its preliminary structure-activity relationship analysis, and laid the foundation for future anti-HIV-1 activity of drug research.}}

HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Design, Synthesis and Antiviral Evaluation of Thiadiazole and Isothiazolone Derivatives

Abstract

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