- Discovery of hydrazone containing thiadiazoles as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors
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Tuberculosis, caused by Mycobacterium tuberculosis, is a serious infectious disease and remains a global health problem. There is an increasing need for the discovery of novel therapeutic agents for its treatment due to the emerging multi-drug resistance.
- Do?an, Hilal,Do?an, ?engül Dilem,Gündüz, Miyase G?zde,Krishna, Vagolu Siva,Lherbet, Christian,Sriram, Dharmarajan,?ahin, Onur,Sar?p?nar, Emin
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- An unprecedented intramolecular to intermolecular mechanistic switch in 1,1-diaminoazines leading to differential product formation during the I2-induced tandem oxidative transformation
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The tautomeric preference of guanylhydrazones towards the azine form induces an unprecedented intramolecular to intermolecular mechanistic switch during the I2-catalyzed oxidative transformation leading to 4,5-disubstituted-3-amino-1,2,4-triazoles in contrast to the reaction of semicarbazones and thiosemicarbazones to form 1,3,4-oxa/thiadiazoles. This intramolecular to intermolecular cyclization shift was established through control experiments and was attributed to the high energy demand (~22 kcal mol-1) for the azine tautomer to adopt the s-cis conformation which is essential for the intramolecular reaction. An I2 induced protocol for an efficient and straightforward synthesis of 4,5-disubstituted-3-amino-1,2,4-triazoles has been developed via tandem oxidative transformation of guanylhydrazones (in its preferentially existing azine tautomeric form) with distinct advantages such as wide substrate scope, use of substoichiometric amounts of iodine, no requirement of external oxidizing agents, base free reaction conditions, short reaction time and moderate to good yields. The role of silver salt in improving the yield and shortening of reaction time was also highlighted.
- Kathuria, Deepika,Gupta, Pankaj,Chourasiya, Sumit S.,Sahoo, Subash C.,Beifuss, Uwe,Chakraborti, Asit K.,Bharatam, Prasad V.
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p. 4129 - 4138
(2019/04/30)
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- Gram-Positive and Gram-Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues
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Desymmetrisation of robenidine (1: N′,2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 μg mL?1. Five analogues were found to be equipotent or more potent than the lead 1. Introduction of an indole moiety resulted in the most active robenidine analogue against methicillin-resistant S. aureus (MRSA), with a MIC of 1.0 μg mL?1. Imine C=NH isosteres (C=O/C=S) were inactive. Monomeric analogues were 16–64 μg mL?1 active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 μg mL?1. A 4-tert-butyl analogue was shown to be active against both Gram-positive and -negative strains at 16–64 μg mL?1. In general, additional modifications with aromatic moieties was poorly tolerated, except with concomitant introduction of an imine C-alkyl group. The activity of these analogues against MRSA and VRE ranged from 8 μg mL?1 to inactive (MIC>128 μg mL?1) with the naphthyl and indole analogues. Gram-negative activity was most promising with two compounds at 16 μg mL?1 against E. coli. Against P. aeruginosa, the highest activity observed was with MIC values of 32 μg mL?1 with another two analogues. Combined, these findings support the further development of the (E)-2-benzylidenehydrazine-1-carboximidamide scaffold as a promising scaffold for the development of antibiotics against Gram-positive and Gram-negative strains.
- Russell, Cecilia C.,Stevens, Andrew,Pi, Hongfei,Khazandi, Manouchehr,Ogunniyi, Abiodun D.,Young, Kelly A.,Baker, Jennifer R.,McCluskey, Siobhann N.,Page, Stephen W.,Trott, Darren J.,McCluskey, Adam
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supporting information
p. 2573 - 2580
(2018/11/27)
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- Rational Design and Synthesis of 1-(Arylideneamino)-4-aryl-1H-imidazole-2-amine Derivatives as Antiplatelet Agents
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Based on previous studies indicating the pharmacophoric role of a hydrazone group and azole rings for antiplatelet aggregation activity, a few series of compounds with both hydrazone and an azole (imidazole) ring in their structures were synthesized, and their platelet aggregation inhibitory effects were evaluated. Two of these 1-(arylideneamino)-4-aryl-1H-imidazole-2-amine derivatives, compounds 4 a [(E)-1-(benzylideneamino)-4-phenyl-1H-imidazol-2-amine] and 4 p [(E)-4-phenyl-1-((thiophen-2-ylmethylene)amino)-1H-imidazol-2-amine], exhibited IC50 values similar to that of acetylsalicylic acid against collagen as a platelet aggregation inducer. Structural comparison of the synthesized compounds revealed that those with a para-substituted phenyl ring on the imidazole were among the most active compounds against platelet aggregation induced by arachidonic acid (AA), and the presence of a thiophene ring in these compounds maximized their antiplatelet activity.
- Amidi, Salimeh,Esfahanizadeh, Marjan,Tabib, Kimia,Soleimani, Zohreh,Kobarfard, Farzad
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p. 962 - 971
(2017/06/27)
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