Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study

Hassan, Ghada S.; El‐Messery, Shahenda M.; Al-Omary, Fatmah A. M.; Al-Rashood, Sarah T.; Shabayek, Marwa I.; Abulfadl, Yasmin S.; Habib, El‐Sayed E.; El‐Hallouty, Salwa M.; Fayad, Walid; Mohamed, Khaled Salah; El-Menshawi, Bassem S.; El‐Subbagh, Hussein I.

doi:10.1016/j.ejmech.2013.05.039

Cited by 62 publications

(19 citation statements)

References 47 publications

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“…Thus, there are various drugs incorporating in their structure the 1,2,4-triazole ring used as antifungal [7,8,9], antiviral [10] agents, aromatase inhibitors [11], etc. Among the 1,2,4-triazole derivatives, the mercapto- and the thione-substituted 1,2,4-triazole ring systems have been studied and so far a variety of biological properties have been reported for a large number of these compounds including antioxidant [12,13,14], antibacterial, antifungal [12,15,16,17,18], anticancer [17,19], hypolipidemic [20], anti-inflammatory [21] activity. Moreover, various S-alkylated 1,2,4-triazole-3-thiones showed antibacterial [22], antifungal [18,22], anti-inflammatory [23], and hypolipidemic [20] activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antioxidant Activity Evaluation of New Compounds from Hydrazinecarbothioamide and 1,2,4-Triazole Class Containing Diarylsulfone and 2,4-Difluorophenyl Moieties

Bărbuceanu

Ilieș

Şaramet

et al. 2014

IJMS

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In the present investigation, new hydrazinecarbothioamides 4–6 were synthesized by reaction of 4-(4-X-phenylsulfonyl)benzoic acids hydrazides (X= H, Cl, Br) 1–3 with 2,4-difluorophenyl isothiocyanate and further these were treated with sodium hydroxide to obtain 1,2,4-triazole-3-thione derivatives 7–9. The reaction of 7–9 with α-halogenated ketones, in basic media, afforded new S-alkylated derivatives 10–15. The structures of the synthesized compounds have been established on the basis of 1H-NMR, 13C-NMR, IR, mass spectral studies and elemental analysis. The antioxidant activity of all compounds has been screened. Hydrazinecarbothioamides 4–6 showed excellent antioxidant activity and 1,2,4-triazole-3-thiones 7–9 showed good antioxidant activity using the DPPH method.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Antioxidant Activity Evaluation of New Compounds from Hydrazinecarbothioamide and 1,2,4-Triazole Class Containing Diarylsulfone and 2,4-Difluorophenyl Moieties

Bărbuceanu

Ilieș

Şaramet

et al. 2014

IJMS

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“…Most of these activities, however, were pulled from batch synthesis efforts reported in the literature, rather than from a directed screening campaign. Of the entire set, 39 had reported MICs below 500 µM, and only 5 had MICs below 50 µM; of these, only a single compound had a MIC below 10 µM 40 . Given that HTS are limited to testing only one concentration, often at 10 µM, it is likely none of these compounds would have been found individually in a screening campaign, and, hence, would not have been identified as a lead series.…”

Section: Resultsmentioning

confidence: 99%

Combinatorial phenotypic screen uncovers unrecognized family of extended thiourea inhibitors with copper-dependent anti-staphylococcal activity

et al. 2016

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The continuous rise of multi-drug resistant pathogenic bacteria has become a significant challenge for the health care system. In particular, novel drugs to treat infections of methicillin-resistant Staphylococcus aureus strains (MRSA) are needed, but traditional drug discovery campaigns have largely failed to deliver clinically suitable antibiotics. More than simply new drugs, new drug discovery approaches are needed to combat bacterial resistance. The recently described phenomenon of copper-dependent inhibitors has galvanized research exploring the use of metal-coordinating molecules to harness copper’s natural antibacterial properties for therapeutic purposes. Here, we describe the results of the first concerted screening effort to identify copper-dependent inhibitors of Staphylococcus aureus. A standard library of 10,000 compounds was assayed for anti-staphylococcal activity, with hits defined as those compounds with a strict copper-dependent inhibitory activity. A total of 53 copper-dependent hit molecules were uncovered, similar to the copper independent hit rate of a traditionally executed campaign conducted in parallel on the same library. Most prominent was a hit family with an extended thiourea core structure, termed the NNSN motif. This motif resulted in copper-dependent and copper-specific S. aureus inhibition, while simultaneously being well tolerated by eukaryotic cells. Importantly, we could demonstrate that copper binding by the NNSN motif is highly unusual and likely responsible for the promising biological qualities of these compounds. A subsequent chemoinformatic meta-analysis of the ChEMBL chemical database confirmed the NNSNs as an unrecognized staphylococcal inhibitor, despite the family’s presence in many chemical screening libraries. Thus, our copper-biased screen has proven able to discover inhibitors within previously screened libraries, offering a mechanism to reinvigorate exhausted molecular collections.

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“…Various synthetic analogs of diaminopyrimidine, including iclaprim, have been developed via three-dimensional structure-based rational design 3,17) Iclaprim is a promising antibacterial drug, which is currently being tested in a Phase III clinical trial. Recently, the discovery of new scaffolds for nonclassical DHFR inhibitors, including thiazoles, 18) quinolinones, 19) and propargyl-linked compounds 20,21) have been reported. Cytotoxic puupehenone (sesquiterpene hydroquinone) and bastadin from the Verongid sponges were reported to inhibit mammalian DHFR.…”

Section: Resultsmentioning

confidence: 99%

The Lactone Form of Stachybotrydial: A New Inhibitor of Dihydrofolate Reductase from <i>Stachybotrys</i> sp. FN298

Kwon

Sohn

Kim

et al. 2014

Biological & Pharmaceutical Bulletin

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Dihydrofolate reductase (DHFR) has been confirmed to be a novel target for antibacterial drug development. In this study, we determined that a fungal metabolite from Stachybotrys sp. FN298 can inhibit the DHFR of Staphylococcus aureus. Its structure was identified as a lactone form of stachybotrydial using mass spectrometry and nuclear magnetic resonance analysis. This compound inhibited S. aureus DHFR with a half-maximal inhibitory concentration of 41 µM. It also prevented the growth of S. aureus and methicillinresistant S. aureus (MRSA) with a minimum inhibitory concentration of 32 µg·mL 1 . To our knowledge, this is the first description of a DHFR inhibitor of microbial origin. The inhibitory function of the lactone form of stachybotrydial highlights its potential for development into a new broad-spectrum antibacterial agent and as an agent against MRSA.

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Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study

Cited by 62 publications

References 47 publications

Synthesis and Antioxidant Activity Evaluation of New Compounds from Hydrazinecarbothioamide and 1,2,4-Triazole Class Containing Diarylsulfone and 2,4-Difluorophenyl Moieties

Synthesis and Antioxidant Activity Evaluation of New Compounds from Hydrazinecarbothioamide and 1,2,4-Triazole Class Containing Diarylsulfone and 2,4-Difluorophenyl Moieties

Combinatorial phenotypic screen uncovers unrecognized family of extended thiourea inhibitors with copper-dependent anti-staphylococcal activity

The Lactone Form of Stachybotrydial: A New Inhibitor of Dihydrofolate Reductase from <i>Stachybotrys</i> sp. FN298

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