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Design, Synthesis, SAR Study, Antimicrobial and Anticancer Evaluation of Novel 2-Mercaptobenzimidazole Azomethine Derivatives

Tahlan S, Narasimhan B, Lim SM, Ramasamy K, Mani V, Shah SAA

Mini Rev Med Chem, 2020;20(15):1559-1571.
PMID: 30179132 DOI: 10.2174/1389557518666180903151849

BACKGROUND: Various analogues of benzimidazole are found to be biologically and therapeutically potent against several ailments. Benzimidazole when attached with heterocyclic rings has shown wide range of potential activities. So, from the above provided facts, we altered benzimidazole derivatives so that more potent antagonists could be developed. In the search for a new category of antimicrobial and anticancer agents, novel azomethine of 2-mercaptobenzimidazole derived from 3-(2- (1H-benzo[d]imidazol-2-ylthio)acetamido)benzohydrazide were synthesized.
RESULTS AND DISCUSSION: The synthesized analogues were characterized by FT-IR, 1H/13C-NMR and MS studies as well C, H, N analysis. All synthesized compounds were evaluated for in vitro antibacterial activity against Gram-positive (B. subtilis), Gram-negative (E. coli, P. aeruginosa, K. pneumoniae and S. typhi) strains and in vitro antifungal activity against C. albicans and A. niger strains by serial dilution method, the minimum inhibitory concentration (MIC) described in μM/ml. The in vitro anticancer activity of synthesized compounds was determined against human colorectal carcinoma cell line (HCT- 116) using 5-fluorouracil as standard drug.
CONCLUSION: In general, most of the synthesized derivatives exhibited significant antimicrobial and anticancer activities. Compounds 8, 10, 15, 16, 17, 20 and 22 showed significant antimicrobial activity towards tested bacterial and fungal strains and compound 26 exhibited significant anticancer activity.

Matched MeSH terms: Benzimidazoles/chemistry*
Side population cells in anaplastic thyroid cancer and normal thyroid

Mahkamova K, Latar NM, Aspinall S, Meeson A

Exp Cell Res, 2019 01 01;374(1):104-113.
PMID: 30465733 DOI: 10.1016/j.yexcr.2018.11.012

Comparison of studies of cells derived from normal and pathological tissues of the same organ can be fraught with difficulties, particular with cancer where a number of different diseases are considered cancer within the same tissue. In the thyroid, there are 4 main types of cancer, three of which arise from follicular epithelial cells; papillary and follicular which are classified as differentiated, and anaplastic which is classified as undifferentiated. One assay that can be utilised for isolation of cancer stem cells is the side population (SP) assay. However, SP studies have been limited in part due to lack of optimal isolation strategies and in the case of anaplastic thyroid cancer (ATC) are further compounded by lack of access to ATC tumors. We have used thyroid cell lines to determine the optimal conditions to isolate viable SP cells. We then compared SP cells and NSP cells (bulk tumour cells without the SP) of a normal thyroid cell line N-thy ori-3-1 and an anaplastic thyroid cancer cell line SW1736 and showed that both SP cell populations displayed higher levels of stem cell characteristics than the NSP. When we compared SP cells of the N-thy ori-3-1 and the SW1736, the SW1736 SP had a higher colony forming potential, expressed higher levels of stem cell markers and CXCR4 and where more migratory and invasive, invasiveness increasing in response to CXCL12. This is the first report showing functional differences between ATC SP and normal thyroid SP and could lead to the identification of new therapeutic targets to treat ATC.

Matched MeSH terms: Benzimidazoles/metabolism
BZD9L1 sirtuin inhibitor: Identification of key molecular targets and their biological functions in HCT 116 colorectal cancer cells

Tan YJ, Lee YT, Mancera RL, Oon CE

Life Sci, 2021 Nov 01;284:119747.
PMID: 34171380 DOI: 10.1016/j.lfs.2021.119747

BZD9L1 was previously described as a SIRT1/2 inhibitor with anti-cancer activities in colorectal cancer (CRC), either as a standalone chemotherapy or in combination with 5-fluorouracil. BZD9L1 was reported to induce apoptosis in CRC cells; however, the network of intracellular pathways and crosstalk between molecular players mediated by BZD9L1 is not fully understood. This study aimed to uncover the mechanisms involved in BZD9L1-mediated cytotoxicity based on previous and new findings for the prediction and identification of related pathways and key molecular players. BZD9L1-regulated candidate targets (RCTs) were identified using a range of molecular, cell-based and biochemical techniques on the HCT 116 cell line. BZD9L1 regulated major cancer pathways including Notch, p53, cell cycle, NFκB, Myc/MAX, and MAPK/ERK signalling pathways. BZD9L1 also induced reactive oxygen species (ROS), regulated apoptosis-related proteins, and altered cell polarity and adhesion profiles. In silico analyses revealed that most RCTs were interconnected, and were involved in the modulation of catalytic activity, metabolism and transcription regulation, response to cytokines, and apoptosis signalling pathways. These RCTs were implicated in p53-dependent apoptosis pathway. This study provides the first assessment of possible associations of molecular players underlying the cytotoxic activity of BZD9L1, and establishes the links between RCTs and apoptosis through the p53 pathway.

Matched MeSH terms: Benzimidazoles/pharmacology*
Fulltext Blood-pressure and cholesterol lowering in persons without cardiovascular disease

Yusuf S, Lonn E, Pais P, Bosch J, López-Jaramillo P, Zhu J, et al.

N Engl J Med, 2016 May 26;374(21):2032-43.
PMID: 27039945 DOI: 10.1056/NEJMoa1600177

BACKGROUND: Elevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol increase the risk of cardiovascular disease. Lowering both should reduce the risk of cardiovascular events substantially.
METHODS: In a trial with 2-by-2 factorial design, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to rosuvastatin (10 mg per day) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. In the analyses reported here, we compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included heart failure, cardiac arrest, or revascularization. The median follow-up was 5.6 years.
RESULTS: The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P=0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P=0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of discontinuation of the trial regimen was similar in the two groups.
CONCLUSIONS: The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.).
Note: Malaysia is a study site (Author: Yusoff K)

Matched MeSH terms: Benzimidazoles/administration & dosage*
Fulltext Selecting optimal second-generation antihistamines for allergic rhinitis and urticaria in Asia

Recto MT, Gabriel MT, Kulthanan K, Tantilipikorn P, Aw DC, Lee TH, et al.

Clin Mol Allergy, 2017;15:19.
PMID: 29118675 DOI: 10.1186/s12948-017-0074-3

Background: Allergic diseases are on the rise in many parts of the world, including the Asia-Pacific (APAC) region. Second-generation antihistamines are the first-line treatment option in the management of allergic rhinitis and urticaria. International guidelines describe the management of these conditions; however, clinicians perceive the additional need to tailor treatment according to patient profiles. This study serves as a consensus of experts from several countries in APAC (Hong Kong, Malaysia, the Philippines, Singapore, Thailand, Vietnam), which aims to describe the unmet needs, practical considerations, challenges, and key decision factors when determining optimal second-generation antihistamines for patients with allergic rhinitis and/or urticaria.
Methods: Specialists from allergology, dermatology, and otorhinolaryngology were surveyed on practical considerations and key decision points when treating patients with allergic rhinitis and/or urticaria.
Results: Clinicians felt the need for additional tools for diagnosis of these diseases and a single drug with all preferred features of an antihistamine. Challenges in treatment include lack of clinician and patient awareness and compliance, financial constraints, and treatment for special patient populations such as those with concomitant disease. Selection of optimal second-generation antihistamines depends on many factors, particularly drug safety and efficacy, impact on psychomotor abilities, and sedation. Country-specific considerations include drug availability and cost-effectiveness. Survey results reveal bilastine as a preferred choice due to its high efficacy and safety, suitability for special patient populations, and the lack of sedative effects.
Conclusions: Compliance to the international guidelines is present among allergists, dermatologists and otorhinolaryngologists; however, this is lower amongst general practitioners (GPs). To increase awareness, allergy education programs targeted at GPs and patients may be beneficial. Updates to the existing international guidelines are suggested in APAC to reflect appropriate management for different patient profiles and varying symptoms of allergic rhinitis and urticaria.

Matched MeSH terms: Benzimidazoles
Orexin-mediated restoration of hippocampal synaptic potentiation in mice with established cocaine-conditioned place preference

Lu GL, Lee MT, Chiou LC

Addict Biol, 2019 11;24(6):1153-1166.
PMID: 30276922 DOI: 10.1111/adb.12672

Orexins (also called hypocretins) are implicated in reward and addiction, but little is known about their role(s) in the association between hippocampal synaptic plasticity and drug preference. Previously, we found that exogenous orexin via OX1 and OX2 receptors can impair low frequency stimulation-induced depotentiation, i.e. restoring potentiation of excitatory synaptic transmission (re-potentiation) in mouse hippocampal slices. Here, we found this re-potentiation in hippocampal slices from mice that had acquired conditioned place preference (CPP) to cocaine. Both 10 and 20 mg/kg of cocaine induced similar magnitudes of CPP in mice and re-potentiation in their hippocampal slices, but differed in their susceptibility to TCS1102, a dual (OX1 and OX2 ) orexin receptor antagonist. TCS1102 significantly attenuated CPP and hippocampal re-potentiation induced by cocaine at 10 mg/kg but not at 20 mg/kg. Nonetheless, SCH23390, an antagonist of dopamine D1-like receptors (D1-likeRs), inhibited the effects induced by both doses of cocaine. SKF38393, a D1-likeR-selective agonist, also induced hippocampal re-potentiation in vitro. Interestingly, this effect was attenuated by TCS1102. Conversely, SCH23390 prevented orexin A-induced hippocampal re-potentiation. These results suggest that endogenous orexins are released in mice during cocaine-CPP acquisition, which sustains potentiated hippocampal transmission via OX1 /OX2 receptors and may contribute to the addiction memory of cocaine. This effect of endogenous orexins, however, may be substituted by dopamine that may dominate hippocampal re-potentiation and CPP via D1-likeRs when the reinforcing effect of cocaine is high.

Matched MeSH terms: Benzimidazoles/pharmacology