- Discovery of new coumarin-based lead with potential anticancer, cdk4 inhibition and selective radiotheranostic effect: Synthesis, 2d & 3d qsar, molecular dynamics, in vitro cytotoxicity, radioiodination, and biodistribution studies
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Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolylbased derivatives were synthesized. A quantitative structure activity relationship (QSAR) model with high predictive power r2 = 0.92, and RMSE = 0.44 predicted five compounds; 2b, 3b, 5a, 9a and 9i to have potential anticancer activities. Compound 2b achieved the best ?G of –15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 2b showed an equilibrium at 0.8 ? after 3.5 ns, while flavopiridol did so at 0.5 ? after the same time (3.5 ns). 2b showed an IC50 of 0.0136 μM, 0.015 μM, and 0.054 μM against MCF-7, A-549, and CHO-K1 cell lines, respectively. The CDK4 enzyme assay revealed the significant CDK4 inhibitory activity of compound 2b with IC50 of 0.036 μM. The selectivity of the newly discovered lead compound 2b toward localization in tumor cells was confirmed by a radioiodination biological assay that was done via electrophilic substitution reaction utilizing the oxidative effect of chloramine-t.131 I-2b showed good in vitro stability up to 4 h. In solid tumor bearing mice, the values of tumor uptake reached a height of 5.97 ± 0.82%ID/g at 60 min p.i.131 I-2b can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity.
- Sarhan, Mona O.,Abd El-Karim, Somaia S.,Anwar, Manal M.,Gouda, Raghda H.,Zaghary, Wafaa A.,Khedr, Mohammed A.
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- Design and development of ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues as Mycobacterium tuberculosis ketol-acid reductoisomerase inhibitors
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Based on our previous finding that the titled compound possesses anti-tuberculosis activity, a series of novel ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues have been synthesized. Amongst the 22 compounds synthesized and tested, 5b, 5c and 6c showed potent inhibitory activity with Ki values of 2.02, 5.48 and 4.72 μM for their target, Mycobacterium tuberculosis (Mt) ketol-acid reductoisomerase (KARI). In addition, these compounds have excellent in vitro activity against Mt H37Rv with MIC values as low as 1 μM. The mode of binding for these compounds to Mt KARI was investigated through molecular docking and dynamics simulations. Furthermore, these compounds were evaluated for their activity in Mt infected macrophages, and showed inhibitory activities with up to a 1.9-fold reduction in growth (at 10 μM concentration). They also inhibited Mt growth in a nutrient starved model by up to 2.5-fold. In addition, these compounds exhibited low toxicity against HEK 293T cell lines. Thus, these compounds are promising Mt KARI inhibitors that can be further optimized into anti-tuberculosis agents.
- George, Shilpa E.,Guddat, Luke W.,Krishna, Vagolu Siva,Nallangi, Radhika,Rekha, Estharla Madhu,Sai Prasad, D. V.,Sriram, Dharmarajan,Zheng, Shan
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- Design, synthesis, biological evaluation, QSAR analysis and molecular modelling of new thiazol-benzimidazoles as EGFR inhibitors
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Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n, 4h, 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67–152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j, 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96–11.91 μM; IC50 erlotinib; 4.15 μM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR.
- Abd El-Karim, Somaia S.,Ahmed, Nesreen S.,Anwar, Manal M.,El-Hallouty, Salwa M.,Srour, Aladdin M.
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supporting information
(2020/08/06)
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- Discovery of a novel nitroimidazolyl-oxazolidinone hybrid with potent anti Gram-positive activity: Synthesis and antibacterial evaluation
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A number of linezolid analogues containing a nitroaryl-1,3,4-thiadiazole moiety, were prepared and evaluated as antibacterial agents against a panel of Gram-positive and Gram-negative bacteria. Among synthesized compounds, nitrofuran analogue 1b exhibited more potent inhibitory activity, with respect to other synthesized compounds and reference drug linezolid. The target compounds were also assessed for their cytotoxic activity against normal mouse fibroblast (NIH/3T3) cells using MTT assay. The results indicated that compound 1c exhibit potent antibacterial activity against Gram-positive bacteria at non-cytotoxic concentrations.
- Khalaj, Ali,Nakhjiri, Maryam,Negahbani, Amir Soheil,Samadizadeh, Marjaneh,Firoozpour, Loghman,Rajabalian, Saeed,Samadi, Nasrin,Faramarzi, Mohammad Ali,Adibpour, Neda,Shafiee, Abbas,Foroumadi, Alireza
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scheme or table
p. 65 - 70
(2011/02/25)
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- Synthesis and biological activity of 5-nitrofuran-containing (1,3,4-thiadiazol-2-yl)piperazine moieties as a new type of anti-Helicobacter pylori heterocycles
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In order to find new and potent drug candidates for the treatment of Helicobacter pylori infections, in this study attention was focused on the synthesis and anti-H. pylori activity of a series of 5-(5-nitrofuran-2-yl)-1,3, 4-thiadiazoles containing piperazinyl functionality at the C-2 position of the 1,3,4-thiadiazole ring. The synthesis of 1-[5-(5-nitrofuran-2-yl)-1,3,4- thiadiazol-2-yl]piperazine derivatives 3a-h and pyrrolidine derivative 3i was achieved with a versatile and efficient synthetic route via 2-chloro-5-(5- nitrofuran-2-yl)-1,3,4-thiadiazole. The inhibitory activity of the new derivatives 3a-i against twenty clinical H. pylori strains was evaluated by the disc diffusion method and compared with the commercially available standard drug metronidazole. Resulting biological data indicated that most compounds exhibited strong inhibitory activity even at doses lower than 2 μg/disc (average zone of inhibition >20 mm) while metronidazole had little or no growth inhibition at this dose. Compound 3c containing the N-benzoylpiperazin-1- yl moiety showed the most potent inhibitory activity.
- Moshafi, Mohammad Hassan,Yahya-Meymandi, Azadeh,Sadat-Ebrahimi, Seyed Esmaeil,Emami, Saeed,Nakhjiri, Maryam,Siavoshi, Farideh,Omrani, Maryam,Vosooghi, Mohsen,Alipour, Eskandar,Shafiee, Abbas,Foroumadi, Alireza
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scheme or table
p. 201 - 210
(2012/01/14)
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- Synthesis and in vitro anti-leishmanial activity of 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]- and 1-[5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl]-4-aroylpiperazines
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The synthesis and anti-leishmanial activity of nitroheteroaryl-1,3,4-thiadiazole-based compounds including 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]-4-aroylpiperazines and 1-[5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl]-4-aroylpiperazines were described. Most of the synthesized compounds exhibited potent anti-leishmanial activity against both promastigote and amastigote forms of Leishmania major at non-cytotoxic concentrations. In general, 5-nitrofuran derivatives were more active than the corresponding 5-nitrothiophene analogues.
- Behrouzi-Fardmoghadam, Mina,Poorrajab, Fatemeh,Ardestani, Sussan Kaboudanian,Emami, Saeed,Shafiee, Abbas,Foroumadi, Alireza
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p. 4509 - 4515
(2008/09/21)
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- Synthesis and anti-Helicobacter pylori activity of 5-(nitroaryl)-1,3,4-thiadiazoles with certain sulfur containing alkyl side chain
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A series of 5-(nitroaryl)-1,3,4-thiadiazoles bearing certain sulfur containing alkyl side chain similar to pendent residue in tinidazole molecule were synthesized and evaluated against Helicobacter pylori using disk diffusion method. The synthesized compounds were also evaluated for their antibacterial, antifungal and cytotoxic effects. Study of the structure-activity relationships of this series of compounds indicated that both the structure of the nitroaryl unit and the pendent group on 2-position of 1,3,4-thiadiazole ring dramatically impact the anti-H. pylori activity. While compound 7a containing 2-[2-(ethylsulfonyl)ethylthio]-side chain from nitrothiophene series was the most potent compound tested against clinical isolates of H. pylori, however, nitroimidazoles 6c and 7c were found to be more promising compounds because of their respectable anti-H. pylori activity besides less cytotoxic effects.
- Foroumadi, Alireza,Rineh, Ardeshir,Emami, Saeed,Siavoshi, Farideh,Massarrat, Sadegh,Safari, Fatemeh,Rajabalian, Saeed,Falahati, Mehraban,Lotfali, Ensieh,Shafiee, Abbas
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scheme or table
p. 3315 - 3320
(2009/04/11)
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- Synthesis and antimycobacterial activity of some alkyl [5-(nitroaryl)-1,3, 4-thiadiazol-2-ylthio]propionates
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Two series of 2- and 3-[5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio, sulfinyl and sulfonyl] propionic acid alkyl esters were synthesized and screened for antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. The MIC values for the compounds showing more than 90% inhibition were determined. The result of comparison between two groups of data exhibited that among the synthesized derivatives, the compound propyl 3-[5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-ylthio]propionate was the most active one (MIC = 1.56 μg ml-1).
- Foroumadi, Alireza,Kargar, Zahra,Sakhteman, Amirhossein,Sharifzadeh, Zahra,Feyzmohammadi, Robabeh,Kazemi, Mahnoush,Shafiee, Abbas
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p. 1164 - 1167
(2007/10/03)
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- Synthesis and in vitro leishmanicidal activity of 2-(5-nitro-2-furyl) and 2-(5-nitro-2-thienyl)-5-substituted-1,3,4-thiadiazoles
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A series of 2-(5-nitro-2-furyl) and 2-(5-nitro-2-thienyl)-5-substituted-1, 3,4-thiadiazoles (5a-d and 6a-j) were synthesized and evaluated against Leishmania major promastigotes using 3H-thymidine incorporation. Most of the compounds showed activity better than the reference drug sodium stibogluconate (Pentostam). The most active compound was 6c (IC50 = 0.1 μM).
- Foroumadi, Alireza,Pournourmohammadi, Shirin,Soltani, Fatemeh,Asgharian-Rezaee, Mitra,Dabiri, Shahriar,Kharazmi, Arsalan,Shafiee, Abbas
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p. 1983 - 1985
(2007/10/03)
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- Synthesis of Thiosemicarbazones under Microwave Irradiation
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Thiosemicarbazones (3) are effectively synthesized in a few minutes by the condensation reaction of aldehydes with thiosemicarbazide under microwave irradiation.
- Cun-De, Wang,Jun, Lu,Xin-Zhong, Shi,Yun-Hua, Feng
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p. 3057 - 3062
(2007/10/03)
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