Computer-aided design and discovery of protein–protein interaction inhibitors as agents for anti-HIV therapy

Protein–protein interactions (PPI) are involved in most of the essential processes that occur in organisms. In recent years, PPI have become the object of increasing attention in drug discovery, particularly for anti-HIV drugs. Although the use of combinations of existing drugs, termed highly active antiretroviral therapy (HAART), has revolutionized the treatment of HIV/AIDS, problems with these agents, such as the rapid emergence of drug-resistant HIV-1 mutants and serious adverse effects, have highlighted the need for further discovery of new drugs and new targets. Numerous investigations have shown that PPI play a key role in the virus’s life cycle and that blocking or modulating them has a significant therapeutic potential. Here we summarize the recent progress in computer-aided design of PPI inhibitors, mainly focusing on the selection of the drug targets (HIV enzymes and virus entry machinery) and the utilization of peptides and small molecules to prevent a variety of protein–protein interactions (viral–viral or viral–host) that play a vital role in the progression of HIV infection.     

Pd-catalyzed selective decarboxylation/C–H activation coupling of aryl acid with thiazole and oxazole directed by 1,2,3-triazole

An efficient palladium-catalyzed selective decarboxylation/C–H activation coupling of aryl acid with thiazole and oxazole under the assistance of 1,2,3-triazole ring were developed. This work provides an effective access to build functionalized 1,2,3-triazoles bearing thiazole and oxazole moieties. This method has good substrate compatibility to compose a series of selective heterocyclic compounds in moderate to good yields.     

Cobalt‐Catalyzed Cross‐Dehydrogenative C(sp2)−C(sp3) Coupling of Oxazole/Thiazole with Ether or Cycloalkane

Direct C5‐alkylation of oxazole/thiazole with ether or cycloalkane has been achieved through a cobalt‐catalyzed cross‐dehydrogenative coupling (CDC) process in moderate to good yields. This transformation represents the first C(sp²)−C(sp³) cross‐coupling at the C5‐position of the oxazole/thiazole via double C−H bond cleavages. Various functional groups on oxazole/thiazole substrates, as well as water and air, are well‐tolerated with this concise and practical protocol, constituting straightforward access to heterocycles with great medicinal significance. A preliminary mechanism involving a radical process has also been proposed.     

Hiv-1 Specific Reverse Transcriptase Inhibitors: why are Tsao-Nucleosides so Unique?

1. INTRODUCTION

AIDS will still be one of the most important challenges for the Scientific Community in the approaching new century. Since the identification, in 1983-84,^1,2 of human immunodeficiency virus (HIV) as the etiological agent of AIDS, significant progress has been made in the treatment of HIV-infected patients. This has been in part due to the discovery and clinical use of an increasing number of anti-HIV drugs. However, while highly active antiretroviral therapy (HAART)³ approaches have reduced the morbidity and mortality, the intertwined problems of drug induced viral resistance, poor compliance with complex regimens and therapy failure continue. Therefore, there remains a pressing need for the development of new antiviral agents that can be used not only as first line therapeutic candidates, but also in the antiretroviral-experienced patient population.     

Generation of 4-substituted coumarins via C–H bond activation under palladium bromide–copper(I) bromide cooperative catalysis

A palladium bromide and copper(I) bromide co-catalyzed reaction of 4-tosyloxy coumarin with benzo[d]oxazole/oxazole/benzo[d]thiazole via C–H activation is described, which generates 4-substituted coumarins in moderate to good yields. 4-Tosyloxy quinolin-2(1H)-one and 2H-pyran-2-one could be applied in this transformation as well.     

Asymmetric biosynthesis of intermediates of anti-HIV drugs

Human immunodeficiency virus (HIV) infection is the fifth most common cause of death and many new HIV infections occur every year. The prevalence of HIV also seriously affects the quality of a patient’s life. More than forty anti-HIV drugs have been put into clinical uses, many of which are chiral molecules with multiple stereogenic centers, for example abacavir, lamivudine, zidovudine, stavudine, tenofovir, atazanavir. However, the chemical synthesis of these chiral intermediates have the disadvantages of low enantiomeric purity and complex synthetic steps. The benefits of asymmetric biosynthesis of chiral drugs include high enantiomeric excess (e.e.), good product selectivity, mild reaction conditions, and less side effects. The biosynthesis of the chiral intermediates of these anti-HIV drugs is thus particularly important. Herein, we review the different sources of enzymes and microbial cells for the asymmetric biosynthesis of the above chiral anti-HIV drug intermediates. We also review recent biotechnology progress in engineering these enzymes and microbial cells with improved biocatalytic activities, including enzyme and cell immobilization, surface display of enzymes, and directed evolution of enzymes. These biotechnology processes enable the efficient biosynthesis of these chiral intermediates, facilitating the industrial production of anti-HIV drugs with reduced costs.     

An ab initio study of the proton affinities of some heteroatomic rings: Imidazole,oxazole, and thiazole

The proton affinities of imidazole, oxazole, and thiazole rings, relevant to the binding of lexitropsins that contain these rings to the minor groove of DNA, are calculated using ab initio (Hartree–Fock) calculations. It is found that the proton affinities decrease in the order imidazole, oxazole, thiazole and that a methyl group substituent increases the proton affinity of imidazole, while a peptidic group decreases it.     

Synthesis and MRSA PK inhibitory activity of thiazole containing deoxytopsentin analogues

The public health care crisis caused by the emergence of drug resistant bacterial strains, e.g., methicillin resistant Staphylococcus aureus (MRSA) has underlined the urgent need to accelerate the discovery of new chemical entities active against antibiotic resistant bacteria. We report here the synthesis of a series thiazole containing deoxytopsentin analogues, which show moderate activity against a target MRSA pyruvate kinase enzyme: an evolutionary conserved hub protein critical for bacterial survival. A Hantzsch thiazole coupling between α-oxo-1H-indole-3-thioacetamides and 2-bromo-1-(1H-indol-3-yl)-ethanones provided facile access to the thiazole containing deoxytopsentin compounds.     

Optical,electrochemical, and sensing properties of polyfluorenes bearing thiazole or oxazole and triphenylamine in the main chain

Polyfluorenes bearing thiazole (PFTH) or oxazole (PFOX) heterocyclic units as well as triphenylamine (TPA) in the main chain were synthesized. The ratio of thiazole or oxazole/TPA in the polymer chain varies from 100/0 to 25/75. The optical properties of polymers depend on thiazole or oxazole contents. Cyclic voltammetry reveals that thiazole or oxazole hinder the oxidation of polymers and only polymers with TPA show reversible oxidation. The Electron Affinities do not practically depend on composition of the polymer chain. The sensing properties of polymers PFTH100 and PFOX100 are investigated toward several cations and anions. Polymers detect two analytes, Fe²⁺ and Hg²⁺. PL quenching shows linear response to Fe²⁺ in wide concentration region 1–800 μΜ. I^? anions quench the emission of polymers. Hg²⁺ turns on the emission of the polymer/I^? complex at concentrations as low as 1 μM. Enhancement of polymer/I^? emission exhibits linear response to Hg²⁺ concentration. PFTH100 is able to detect Fe²⁺ and Hg²⁺ that coexist in a solution. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 243–254     

靶向整合过程不同步骤的HIV-1整合酶抑制剂的结构类型和研究进展

HIV-1整合酶是病毒复制所必需的三个基本酶之一, 为病毒所特有, 人体无对应的酶, 因此整合酶是理想的抗HIV药物设计的新靶标. HIV-1整合酶催化病毒DNA插入宿主染色体的过程涉及到整合酶与前病毒DNA形成整合前复合物、病毒DNA的3’末端切断和DNA链转移等步骤, 目前研究得最多的HIV-1整合酶抑制剂是抑制链转移反应的芳基二酮酸化合物, 其中的电子等排体衍生物Raltegravir (MK-0518)于2007年10月被美国食品药品管理局(FDA)批准上市, 而GS-9137处于三期临床试验, 此外还有多个处于临床前研究和临床阶段的药物. 根据抑制剂的不同作用机理, 本综述介绍了近年来所报道的HIV-1整合酶抑制剂的结构类型、药效团模型、研究进展及化学合成, 将整合酶抑制剂分为链转移反应抑制剂、整合酶-DNA结合抑制剂、整合酶3’端切除反应抑制剂、非专一性整合酶抑制剂以及多肽类抑制剂等几大类. 其中链转移反应抑制剂结构类型最丰富、发展最快. 整合酶抑制剂的出现丰富了高效抗逆转录病毒疗法(HAART), 为多重抗药性艾滋病患者提供了新的有效的治疗方案.     

Synthesis of libraries of thiazole, oxazole and imidazole-based cyclic peptides from azole-based amino acids. A new synthetic approach to bistratamides and didmolamides

Treatment of a 1 : 1 mixture of the thiazole-based amino acids 8a and 8b with FDPP-i-Pr(2)NEt in CH(3)CN gave a mixture of the cyclic trimers 14, 15, 16 and 17 and the cyclic tetramers 19 and 23 in the ratio 2 : 7 : 5 : 8 : 1 : 1 and in a combined yield of 70%. Separate coupling reactions between the bisimidazole amino acid 45 and the thiazole/oxazole amino acids 43a and 42a in the presence of FDPP-i-Pr(2)NEt led to the bisimidazole based cyclic trimers 55 and 57 respectively (54-57%) and to the cyclic tetramer 56 (8-11%). Similar coupling reactions involving the bisthiazole and bisoxazole amino acids 49 and 47 with the imidazole/oxazole/thiazole amino acids 41a, 42a and 43a gave rise to the library of oxazole, thiazole and imidazole-based cyclic peptides 58, 59, 60, 61, 62, 63, 64 and 65. A coupling reaction between the bisthiazole amino acid 49 and the oxazole amino acid 73 led to an efficient (36% overall) synthesis of bistratamide H (67) found in the ascidian Lissoclinum bistratum. Coupling reactions involving oxazolines with thiazole amino acids were less successful. Thus, a coupling reaction between the phenylalanine-based oxazoline amino acid 71a and either the thiazole amino acid 8a or the bisthiazole amino acid 74 gave only a 2% yield of the cyclic hexapeptide didmolamide A (4) found in the ascidian Didemnum molle. Didmolamide B (68) was obtained in 9% yield from a coupling reaction between 74 and the phenylalanine threonine amino acid 72, using either FDPP or DPPA.     

新型非拟肽磺胺类HIV蛋白酶抑制剂Darunavir的研究进展

综述新型非拟肽磺胺类人类免疫缺陷病毒(HIV)蛋白酶抑制剂Darunavir (TMC-114)的发现, 抗病毒的活性, 分子模拟以及结构优化的研究进展. Darunavir不但对野生型的HIV蛋白酶有很好的抑制活性, 而且对多种抗性突变的HIV蛋白酶也有良好的活性, 是针对耐药性HIV所开发的新药.     

Acyclovir phosphoramidates as potential anti-HIV drugs

A number of phosphoramidate derivatives of acyclovir (ACV) were obtained. These compounds revealed themselves as latent forms of acyclovir monophosphate (ACV-MP). The optimized route to the title phosphoramidates involves the synthesis of intermediate phosphorodichloridates followed by their treatment with various amines. The compounds obtained showed moderate antiviral activity both in vitro in a controlled system of secure screening for anti-HIV agents and in a tissue system enabling ex vivo determination of the efficiency of the drug and its effect on HIV replication in two weeks.     

Total and Semi‐Syntheses of Antimicrobial Thuggacin Derivatives

The total and semi‐synthesis of 13 new macrolactones derived from thuggacin, which is a secondary metabolite from the myxobacterium Sorangium cellulosum, are reported. The thuggacins have attracted much attention due to their strong antibacterial activity, particularly towards Mycobacterium tuberculosis. This study focuses on 1) thuggacin derivatives that cannot equilibrate by transacylation between the three natural thuggacins A–C, 2) the roles of the thiazole ring, and 3) the hexyl side chain at C2. Semi‐synthetic O‐methylation at C17 suppressed the transacylations without a substantial loss of antibacterial activity. Exchanging the C17–C25 side chain for simplified hydrophobic chains led to complete loss of antibacterial activity. Exchange of the thiazole by an oxazole ring or removal of the hexyl side chain at C2 had no substantial effect on the biological properties.     

Synthesis of antimicrobial agents of tetra-substituted thiophenes from ethyl 5-(2-bromoacetyl)-4-phenyl-2-(phenylamino)thiophene-3-carboxylate

5-(2-Bromoacetyl)-2,3,4-trisubstituted-thiophene was used as a synthetic intermediate to prepare a series of thiophene derivatives and thiophene incorporating oxazole, imidazole, thiazole, pyrrole, and pyridine rings via substitution and cyclo-condensation reactions. The data were extracted from the spectra of the resulting products confirmed their suggested structures. The newly synthesized compounds were screened to evaluate their in vitro antimicrobial activity vs several positive and negative gram bacteria and fungi. The screening data revealed that the thiophene derivative 7a , incorporating a thiazole ring, displayed strong activity against all tested microorganisms when compared with the antibiotics used.