Synthesis, cytotoxicity, pharmacokinetic profile, binding with DNA and BSA of new imidazo[1,2-a]pyrazine-benzo[d]imidazol-5-yl hybrids

Abstract

Novel derivatives possessing imidazo[1,2-a]pyrazine and 1H-benzo[d]imidazole scaffolds were synthesized using Suzuki-Miyaura cross-coupling reactions. In vitro anticancer activities against NCI-60 cancer cell panels were tested at 10 µM concentration. The best results were obtained from substitution of two 1-cyclohexyl-1H-benzo[d]imidazole groups present at C-6 and C-8 positions of imidazo[1,2-a] pyrazine (31). Compound 31 was found to be cytotoxic against 51 cell lines and cytostatic against 8 cell lines with broad range of growth inhibitions (−98.48 to 98.86%). GI 50 value of compound 31 was found in the range of 0.80-2.87 µM for 59 human cancer cell lines at five-dose concentration levels. DNA binding study of potent compound 31 was suggested that this compound was intercalated into DNA base pairs with binding constant of 1.25 × 10 4 M −1. Compound 31 showed effective binding with bovine serum albumin (BSA) and presented binding constant value of 3.79 ×10 4 M-1. Pharmacokinetic studies revealed that all compounds are following Lipinski's rule of five and expected to be orally active. Cancer is one of the major reasons for death globally. Millions of people suffer or die from cancer each year, and there is no particular good medication available at present 1. Cancer has significant economic impact, which is increasing gradually. In the field of cancer treatment, chemists have great challenges to discover new and efficient compounds with strong and broad-spectrum anticancer activity. Heterocyclic ring systems play significant role in the discovery of novel bioactive substances due to their minimal side effects and effective at small doses. Heterocyclic moieties are widely present in various natural bioactive compounds 2. Undesirable side effects, toxicity, drug resistance, and low bioavailability are some of the major known problems for currently available anticancer agents 3. Therefore, there is an urgent need for the discovery of more efficient and selective anticancer agent. The biological potential of these heterocycles towards cancer cells has been stated with diverse mechanism of action. Most of the anticancer candidates bind with DNA double-strand and interfere with replication and transcription, thus, interrupt DNA function and alter the cell division. These candidates show interaction between adjacent base pairs or bind with grooves of DNA. These candidates share similar structural features, for example, the presence of planarity in structure, which can help the molecule to bind with DNA through insertion between base-pairs. The basic chain connected with these heterocyclic moieties plays a significant role in the selectivity and affinity 4. Due to their high affinity, the discovery of novel DNA intercalator for cancer therapy is a crucial goal in the medicinal chemistry. These intercalators comprise anthracyclines 5,6 (e.g. doxorubicin and mitoxantrone), ellipticine 7 and acridine derivatives (e.g. amsacrine) 8 , used in the cancer therapy of acute leukemia, breast, and ovarian cancers. On account of r...

Visible-light driven regioselective synthesis, characterization and binding studies of 2-aroyl-3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidines with DNA and BSA using biophysical and computational techniques

“…CD spectrum of DNA comprises two characteristic bands; a positive band at 275 nm due to π–π base stacking and a negative band at 245 nm due to helicity of B form DNA 44 . Intercalation of small molecules with DNA enhances the intensities of both the bands, however, groove binding shows little or no perturbations on the base stacking and helicity bands, stabilizing the right-handed helical structure of ct-DNA.…”

Synthesis and photobiological applications of naphthalimide–benzothiazole conjugates: cytotoxicity and topoisomerase IIα inhibition

“…[14][15][16] Previously, various hybrids of benzimidazole and naphthalimide moieties, 17 combined without any linker, have been synthesized and were evaluated for their anticancer activities. These hybrids revealed more activity than hybrids of benzimidazole and imidazo[1,2-a]pyrazine, 18,19 or naphthalimide and phenanthroimidazole. 20,21 These hybrids also indicated higher antiproliferative activity than the clinical trial drug, amonade.…”

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…A series of compounds reported by Singh et al explored the benzimidazole scaffold for the synthesis of DNA-interactive anticancer candidates [ 104 , 105 , 106 , 107 ]. In one such effort, naphthalimide–benzimidazole hybrid compounds were prepared as potential antiproliferative agents against the NCI panel of 60 human cancer cell lines [ 104 ].…”

“…Circular dichroism studies with compounds 111 and 112 in the presence of calf thymus DNA suggested an intercalative mode of DNA binding for these molecules. In an extension of the work described above, compound 113 displayed broad spectrum activity with GI 50 values in the range between 0.80–2.87 μM against 59 human cancer cell lines [ 106 ]. This compound increased the melting temperature of calf thymus DNA by 12 °C.…”

“…Compound 107 displayed greater potency against A549 cells (IC 50 = 1.85 µM) compared to compound 104 (IC 50 = 5.02 µM). As above, spectroscopic experiments were used to provide evidence for the binding of these compounds to DNA via intercalation.A series of compounds reported by Singh et al explored the benzimidazole scaffold for the synthesis of DNA-interactive anticancer candidates[104][105][106][107]. In one such effort, naphthalimide-benzimidazole hybrid compounds were prepared as potential antiprolif-…”