Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH

Abdullah, Iskandar; Chee, Chin Fei; Lee, Yean Kee; Thunuguntla, Siva Sanjeeva Rao; Reddy, K. Satish; Nellore, Kavitha; Antony, Thomas; Verma, Jaya; Mun, Kong Wai; Othman, Shatrah; Subramanya, Hosahalli; Rahman, Noorsaadah Abd.

doi:10.1016/j.bmc.2015.05.051

Cited by 43 publications

(15 citation statements)

References 26 publications

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“…In their studies, the biphenyl ring system was retained for activity and the substitution pattern (-F, -CF 3 and -OCF 3 ) on the biphenyl ring system was the most significant feature for better human DHODH inhibitory activity. Similar results were drawn by Abdullah (Abdullah et al, 2015) and Batt (Batt et al, 1998). It should be mentioned that in some investigations, the biphenyl ring system or biphenyl with an additional linker system reduced inhibitory activity because of the steric constraints of the binding pocket in this area (Zhu et al, 2015).…”

Section: Design and Dockingsupporting

confidence: 79%

“…Through modulating pyrimidine biosynthesis, inhibitors of dihydroorotate dehydrogenase (DHODH) have proved to be clinically useful in the treatment of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, transplant rejection and psoriatic arthritis (Norman, 2013;Munier-Lehmann et al, 2013). Many inhibitors have also been investigated to treat cancer (Dell, 1998;Hurt et al, 2006;Vyas et al, 2014;Abdullah et al, 2015) and viral (Zhang et al, 2012) and parasite infections (i.e. malaria) (Seymour et al, 1994;Booker et al, 2010;Skerlj et al, 2011), as well being used as antifungal agents (Gustafson et al, 1996), antibiotics (Marcinkeviciene et al, 2000;Copeland et al, 2000) and in crop science (Longhurst et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…1] was the most promising DHODH inhibitor that was potent against a number of types of cancer (including human colon, breast, lung, head and neck, and stomach xenografts in athymic mice), but was withdrawn from development because of toxicity (Dell, 1998;Maroun et al, 1993). Even so, DHODH is still an important target for anticancer drug discovery and in antihypertensive and anti-inflammation drug development, since these enzymes share a common role in the DNA replication and repair mechanisms (Abdullah et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, crystal structure andin vitrocytotoxic properties of a novel Schiff base derived from indole and biphenyl

Tan

Xing

et al. 2017

Acta Crystallogr C

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A novel and potentially active dihydroorotate dehydrogenase (DHODH) inhibitor, namely 3-({(E)-[(E)-1-(biphenyl-4-yl)ethylidene]hydrazinylidene}methyl)-1H-indole (BEHI) acetonitrile disolvate, CHN·2CHCN, has been designed and synthesized. The structure of BEHI was characterized by elemental analysis, Q-TOF (quadrupole time-of-flight) MS, NMR, UV-Vis and single-crystal X-ray diffraction. The antitumour activity of the target molecule was evaluated by the MTT method. Results indicated that BEHI exhibited rather potent cytotoxic activity against human A549 (IC = 20.5 µM) and mouse breast 4T (IC = 18.5 µM) cancer cell lines. Meanwhile, to rationalize its potencies in the target, BEHI was docked into DHODH and the interactions with the active site residues were analyzed. Single-crystal structure analysis indicated that hydrogen bonds are present only between BEHI and acetonitrile solvent molecules in the asymmetric unit. The interplay of weak π-π stacking and weak C(N)-H...π interactions between neighbouring BEHI molecules play crucial roles in the formation of the final supramolecular frameworks.

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Section: Design and Dockingsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, crystal structure andin vitrocytotoxic properties of a novel Schiff base derived from indole and biphenyl

Tan

Xing

et al. 2017

Acta Crystallogr C

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“…Also it exhibited inhibition of tubulin polymerisation upto 71.27% with IC 50 values 1.71 μM against nocodazole (1.75 µM) as the standard drug. Abdullah et al carried out the synthesis of new benzimidazole derivatives as potential dual inhibitors for PARP‐1 and dihydroorotate dehydrogenase (DHODH) enzymes (Schemes and ). Compounds 318c and 316b showed most potent results against veliparib and brequinar as reference inhibitors.…”

Section: Pharmacological and Synthetic Profiles Of Benzimidazole Derimentioning

confidence: 99%

Benzimidazole Scaffold as Anticancer Agent: Synthetic Approaches and Structure–Activity Relationship

Shrivastava

Naim

Alam

et al. 2017

Archiv der Pharmazie

124

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Cancer, also known as malignant neoplasm, is a dreadful disease which involves abnormal cell growth having the potential to invade or spread to other parts of the body. Benzimidazole is an organic compound that is heterocyclic and aromatic in nature. It is a bicyclic compound formed by the fusion of the benzene and imidazole ring systems. It is an important pharmacophore and a privileged structure in medicinal chemistry. According to the World Health Organisation (2015 survey), one in six deaths is due to cancer around the globe, accounting for 8.8 million deaths of which 70% of the cases were from low- and middle-income countries. In the efforts to develop suitable anticancer drugs, medicinal chemists have focussed on benzimidazole derivatives. This review article covers the current development of benzimidazole-based anticancer agents along with the synthetic approaches and structure-activity relationships (SAR).

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“…Together, the observation of prolonged S-phase arrest, the upregulation of the DDR response in HHQ-exposed cultures, the conserved nature of the mammalian and E. huxleyi PARP catalytic site (Fig. S16), and the chemical structural similarities of HHQ to known inhibitors of both PARP and DHODH with core benzimidazole moieties 51 , collectively suggest that HHQ may function simultaneously to inhibit both PARP and DHODH activity in E. huxleyi.…”

Section: Hhqmentioning

confidence: 93%

Bacterial quorum sensing signal arrests phytoplankton cell division and protects against virus-induced mortality

Pollara¹,

Becker²,

Nunn

et al. 2020

Preprint

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Interactions between phytoplankton and heterotrophic bacteria fundamentally shape marine ecosystems. These interactions are driven by the exchange of compounds, however, linking these chemical signals, their mechanisms of action, and resultant ecological consequences remains a fundamental challenge. The bacterial signal 2-heptyl-4-quinolone (HHQ), induces immediate cellular stasis in the coccolithophore, Emiliania huxleyi, however, the mechanism responsible remains unknown. Here, we show that HHQ exposure leads to the accumulation of DNA damage in phytoplankton and prevents its repair. While this effect is reversible, HHQ-exposed phytoplankton are also protected from viral mortality, ascribing a new role of quorum sensing signals in regulating multi-trophic interactions. Further results demonstrate global HHQ production potential and the first in situ measurements of HHQ which coincide with areas of enhanced micro- and nanoplankton biomass. Our results support bacterial communication signals as emerging players, providing a new mechanistic framework for how compounds may contribute to structure complex marine microbial communities.

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Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH

Cited by 43 publications

References 26 publications

Design, synthesis, crystal structure andin vitrocytotoxic properties of a novel Schiff base derived from indole and biphenyl

Design, synthesis, crystal structure andin vitrocytotoxic properties of a novel Schiff base derived from indole and biphenyl

Benzimidazole Scaffold as Anticancer Agent: Synthetic Approaches and Structure–Activity Relationship

Bacterial quorum sensing signal arrests phytoplankton cell division and protects against virus-induced mortality

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