Novel 1,2,3-thiadiazole derivatives as HIV-1 NNRTIs with improved potency: Synthesis and preliminary SAR studies

Zhan, Peng; Liu, Xinyong; Li, Zhenyu; Fang, Zengjun; Li, Zhong; Wang, Defeng; Pannecouque, Christophe; Clercq, Erik De

doi:10.1016/j.bmc.2009.07.004

Cited by 76 publications

(31 citation statements)

References 26 publications

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“…Thiazole and thiadiazole derivatives are known to exhibit various biological activities, such as anti-allergy [4], antihypertensive [5], anti-in-flammatory [6][7], anti-schizophrenia [8], antifungal [9], antibacterial [10], antimicrobial [11][12][13], analgesic [14], anti-HIV [15], anticonvulsant [16], antidepressant [17], and anti-cancer [18][19][20][21] properties. Other uses of heterocyclic compounds containing nitrogen and sulfur include manufacturing biocides, dyes [22][23][24], and plant-growth regulators [25].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Novel 1,3-Thiazole and 2-Amino-1,3,4-Thiadiazole Derivatives

Şahin

Tahtacı

2014

Maced. J. Chem. Chem. Eng.

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Thiosemicarbazone derivatives 3a-e were synthesized by the reaction of various aldehydes 1a-e with 4-methyl thiosemicarbazide 2 in 78% to 90% yield. Then, the thiazole moieties of the target materials 5a-e were obtained in high yields (71-93%) using the Hantzsch reaction utilizing thiosemicarbazone derivatives 3a-e with ethyl-2-chloroacetoacetic ester. The substituted nitrile derivatives 7a-e were obtained in moderate to high yield (58-84%) from the reaction of compounds 5a-e with chloroacetonitrile by the nucleophilic aliphatic substitution reaction in the presence of anhydrous potassium carbonate. Finally, substituted 2-amino-1,3,4-thiadiazole compounds 9a-e were obtained in moderate to good yields (51-62%) from the reaction of thiosemicarbazide with substituted nitrile derivatives 7a-e. As a result, compounds that all share a high disposition for biological activities were obtained. The structures of the newly synthesized compounds were confirmed by IR, 1 H NMR, 13 C NMR, elemental analysis, and mass spectrometric techniques.Keywords: thiosemicarbazone; 1,3-thiazole; 2-amino-1,3,4-thiadiazole; Hantzsch reaction СИНТЕЗА И КАРАКТЕРИЗАЦИЈА НА НОВИ ДЕРИВАТИ НА 1,3-ТИАЗОЛ И 2-АМИНО-1,3,4-ТИАДИАЗОЛТиосемикарбазонските деривати 3a-e беа синтетизирани при реакција на разни алдехиди 1a-e со 4-метилтиосемикарбазид 2 со принос од 78 до 90%. Тиазолските прстени на целните соединенија 5a-e беа добиени со висок принос од 71-93% со реакцијата на Hantzsch со примена на тиосемикарбазонските деривати 3a-e и етил-2-хлороацетооцетен естер. Супституираните нитрилни деривати 7a-e беа добиени со умерен до висок принос при реакција на соединенијата 5a-e со хлороацетонитрил при нуклеофилна алифатична супституција во присуство на безводен калиумкарбонат. Конечно, супституираните 2-амино-1,3,4-тиодиазолните соединенија 9a-e беа добиени со умерен до добар принос (51-62%) при реакција на тиосемикарбазид со супституирани нитрилни деривати 7a-e. Сите овие добиени соединенија покажуваат висока биолошка активност. Структурите на новосинтетизираните соединенија беа потврдени по пат на IR, 1 H NMR, 13 C NMR, елементарна анализа и масеноспектрометриски техники.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Novel 1,3-Thiazole and 2-Amino-1,3,4-Thiadiazole Derivatives

Şahin

Tahtacı

2014

Maced. J. Chem. Chem. Eng.

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“…Besides, regardless of in 1,2,3-thiadiazole or 1,2,4-triazine series, the N-(2-fluorophenyl)acetamide derivatives (38, 40 and 42) were always less potent than the N-(2-chlorophenyl)acetamide counterparts (37, 39 and 41) [51][52][53]. Therefore, a major challenge moving forward will be where and how to install fluorine in a rational manner to best optimize molecular properties.…”

Section: Expert Opinionmentioning

confidence: 96%

“…As another example, in the optimization of arylazolyl (azinyl)thioacetanilide-based NNRTIs [51][52][53][54][55], we found that the introduction of 2,4-difluorophenyl group (1,2,3-thiadiazole thioacetanilide 37,38) into the hydrophobic area lined by electron-rich aromatic residues could decrease the anti-HIV activity substantially, as compared with the 2,4-dibromophenyl analogs 39 and 40 [51,52]. Besides, regardless of in 1,2,3-thiadiazole or 1,2,4-triazine series, the N-(2-fluorophenyl)acetamide derivatives (38, 40 and 42) were always less potent than the N-(2-chlorophenyl)acetamide counterparts (37, 39 and 41) [51][52][53].…”

Section: Expert Opinionmentioning

confidence: 99%

Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419

Meng¹,

Liu²,

Huang³

et al. 2015

Expert Opinion on Therapeutic Patents

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Diarylpyrimidine (DAPY) derivatives, one family of HIV non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with superior activities against wild-type (WT) HIV-1 and NNRTI-resistant strains, have attracted much attention in the past decade. A series of DAPY derivatives featuring a fluorine atom on the central ring were reported as novel NNRTIs in the patent WO2014072419. Some compounds exhibited robust potency against both WT and mutant strains, which were approximately equal to or higher than those of the reference drug TMC120. Moreover, it has become evident that fluorinated molecules have a remarkable record in many other potent NNRTIs. Thus, this survey provides a sampling of renowned fluorinated NNRTIs and their mode of action, with an analysis clarifying the functional roles and impact of fluorine substitution on antiviral potency. We envision that fluorinated NNRTIs will play a continuing role in affording anti-HIV drug candidates for therapeutic applications.

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“…Structural and structure-activity relationship (SAR) studies of the known arylazolylthioacetanilides illustrated in the literature [14][15][16][17][18][19][20][21][22] have pointed to the presence of key chemical features that correlated with the RT inhibitory ability, i.e., the aryl group linked to the azole core tted into the important hydrophobic pocket and the carbonyl group of the amide were able to establish a key hydrogen bond through interaction with the backbone N-H of K103. These functionalities are maintained in a spatial arrangement within the NNRTI binding pocket by positioning a heterocyclic central core in the arylazolylthioacetanilides.…”

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confidence: 99%

“…There are differences in the electronic and conformational contribution of the ve-membered heterocyclic moiety to the binding of the inhibitors to RT. 15 Additional branching moieties, such as the N-substituted phenyl moiety located at the protein/solvent interface near a region of the protein known to be exible, can be present or extended to further optimize the potency and/or physicochemical properties.…”

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confidence: 99%

Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

et al. 2013

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In continuation of our endeavors to develop new, potent, selective, and less toxic anti-HIV agents, we describe our structure-based bioisosterism design, synthetic strategy, and structure-activity relationship (SAR) studies that led to the identification of pyridazinylthioacetamides, a novel class of NNRTIs, isosteres of arylazolylthioacetanilide derivatives. Nearly all of the tested compounds inhibited HIV-1 strain IIIB replication in the lower micromolar concentration range (EC 50 : 0.046-5.46 mM). Notably, the most promising compound 8k exhibited extremely potent inhibitory activity against HIV-1 replication with an EC 50 value of 0.046 mM, CC 50 of 99.9 mM and the viral selectivity index amounted to 2149.These values were much better than those of NVP (EC 50 ¼ 0.09 mM) and DDC (EC 50 ¼ 1.04 mM).Compound 8k also exhibited moderate inhibition of enzymatic activity with an IC 50 value of 4.06 mM, which was of the same order of magnitude as that of NVP (2.74 mM). Docking calculations were also performed to investigate the binding mode of compound 8k into the non-nucleoside binding site of HIV-1 RT and to rationalize some SARs.

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Novel 1,2,3-thiadiazole derivatives as HIV-1 NNRTIs with improved potency: Synthesis and preliminary SAR studies

Cited by 76 publications

References 26 publications

Synthesis and Characterization of Novel 1,3-Thiazole and 2-Amino-1,3,4-Thiadiazole Derivatives

Synthesis and Characterization of Novel 1,3-Thiazole and 2-Amino-1,3,4-Thiadiazole Derivatives

Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419

Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

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