Current Therapeutic Strategies for the Management of Benzodiazepine (BZD) Withdrawal Syndrome: A Review.

Benzodiazepines are commonly prescribed drugs for numerous indications such as epilepsy, anti-anxiety, sleep aids, sedatives, and hypnotics. Although the well-tolerated effects of benzodiazepine are seen in many clinical instances, the severity of side effects reduces its quantifiable use. Benzodiazepines, which are medically useful but theoretically unsafe, are frequently recommended by medical practitioners for psychotic patients but have misuse and dependence liabilities. It is impelled as a debateable topic globally about which no one talks. These drugs are also known as silent killers because abruptly stopping them can result in tremors, muscle spasticity, and life-frightening seizures. These drugs are beneficial as well as risky. Nonclinical treatment is simple and well suited and provides support for patients suffering from side effects generated by benzodiazepine withdrawal. This review mainly focuses on antipsychotic drugs and their mechanisms, mortality, withdrawal, abuse, and management via clinical and nonclinical therapies.

Synthesis and biological evaluation of heterocyclic 1,2,4-triazole scaffolds as promising pharmacological agents.

BACKGROUND: Triazole is an important heterocyclic moiety that occupies a unique position in heterocyclic chemistry, due to its large number of biological activities. It exists in two isomeric forms i.e. 1,2,4-triazole and 1,2,3-triazole and is used as core molecule for the design and synthesis of many medicinal compounds. 1,2,4-Triazole possess broad spectrum of therapeutically interesting drug candidates such as analgesic, antiseptic, antimicrobial, antioxidant, anti-urease, anti-inflammatory, diuretics, anticancer, anticonvulsant, antidiabetic and antimigraine agents. METHODS: The structures of all synthesized compounds were characterized by physicochemical properties and spectral means (IR and NMR). The synthesized compounds were evaluated for their in vitro antimicrobial activity against Gram-positive (B. subtilis), Gram-negative (P. aeruginosa and E. coli) bacterial and fungal (C. albicans and A. niger) strains by tube dilution method using ciprofloxacin, amoxicillin and fluconazole as standards. In-vitro antioxidant and anti-urease screening was done by DPPH assay and indophenol method, respectively. The in-vitro anticancer evaluation was carried out against MCF-7 and HCT116 cancer cell lines using 5-FU as standards. RESULTS, DISCUSSION AND CONCLUSION: The biological screening results reveal that the compounds T5 (MICBS, EC = 24.7 µM, MICPA, CA = 12.3 µM) and T17 (MICAN = 27.1 µM) exhibited potent antimicrobial activity as comparable to standards ciprofloxacin, amoxicillin (MICCipro = 18.1 µM, MICAmo = 17.1 µM) and fluconazole (MICFlu = 20.4 µM), respectively. The antioxidant evaluation showed that compounds T2 (IC50 = 34.83 µg/ml) and T3 (IC50 = 34.38 µg/ml) showed significant antioxidant activity and comparable to ascorbic acid (IC50 = 35.44 µg/ml). Compounds T3 (IC50 = 54.01 µg/ml) was the most potent urease inhibitor amongst the synthesized compounds and compared to standard thiourea (IC50 = 54.25 µg/ml). The most potent anticancer activity was shown by compounds T2 (IC50 = 3.84 µM) and T7 (IC50 = 3.25 µM) against HCT116 cell lines as compared to standard 5-FU (IC50 = 25.36 µM).

Synthesis, Characterization, Antimicrobial and Anticancer Studies of Metal Complexes of 2-methoxy-4-((3-methylpyridin-2-ylimino)methyl)phenol.

BACKGROUND: Being derived from primary amine and aromatic aldehyde, Schiff base and their complexes have an imperative role in the improvement of inorganic chemistry, which are broadly studied as coordination compounds and are gradually becoming more important in biochemical and analytical applications. METHODS: They have also been used for antibacterial, antifungal, anticancer, antitubercular activities. Novel synthesised Schiff's base 2-methoxy-4-((3-methylpyridin-2-ylimino)methyl)phenol (SB) and its metal complexes (Zn[II], Cu[II], Co[II] and Ni[II]) were characterised by UV, IR and NMR spectroscopy. Formation of the Schiff base and the metal (Zn[II], Cu[II], Co[II] and Ni[II]) chelates was supported by spectral and analytical data. The ligand and metal complexes have been screened for their antibacterial activity against Staphylococcus aureus, Salmonella typhi, Escherichia coli, Klebsiella pneumoniae and antifungal activity against the fungi Candida albicans and Aspergillus niger. Further, the synthesised compounds were also screened for antiproliferative activity against the human colorectal carcinoma (HCT116) cell line using the Sulforhodamine B assay. RESULT: Metal complexes formed were found to enhance the potency of the Schiff base due to coordination with a copper complex, showing better activity than others. CONCLUSION: Copper complex was observed to be more potent than other complexes against all the pathogenic microbes and cancer cell line (HCT116).

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

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.

4-(2-(1H-Benzo[d]imidazol-2-ylthio)acetamido)-N-(substituted phenyl)benzamides: design, synthesis and biological evaluation.

BACKGROUND: Dihydrofolate reductase (DHFR) is an important target for antimetabolite class of antimicrobials because it participates in purine synthesis. 2-mercaptobenzimidazole (2MBI) has similar structural features as purine nucleotides. Given that benzimidazole and similar heteroaromatics have been broadly examined for their anticancer potential, so, we hereby report the design, synthesis and biological studies (i.e. antimicrobial and anticancer studies) of 2MBI derivatives. METHODOLOGY: The antimicrobial activity of synthesized 2MBI derivatives were evaluated against Gram positive and Gram negative bacterial species as well as fungal species by tube dilution technique whereas their anticancer activity was assessed against human colorectal carcinoma cell line (HCT116) by Sulforhodamine B (SRB) assay. They were also structurally characterized by IR, NMR, MS and elemental analyses. RESULTS DISCUSSION AND CONCLUSION: The antimicrobial activity findings revealed that compound N1 (MIC bs,st, ca = 1.27, 2.54, 1.27 µM), N8 (MIC ec = 1.43 µM), N22 (MIC kp,an = 2.60 µM), N23 and N25 (MIC sa = 2.65 µM) exhibited significant antimicrobial effects against tested strains, i.e. Gram-positive, Gram-negative (bacterial) and fungal strains. The anticancer screening results demonstrated that compounds N9, N18 (IC50 = 5.85, 4.53 µM) were the most potent compounds against cancer cell line (HCT116) even more than 5-FU, the standard drug (IC50 = 9.99 µM).

Antimicrobial potential of 1H-benzo[d]imidazole scaffold: a review.

BACKGROUND: Benzimidazole is a heterocyclic moiety whose derivatives are present in many of the bioactive compounds and posses diverse biological and clinical applications. Benzimidazole agents are the vital pharmacophore and privileged sub-structures in chemistry of medicine. They have received much interest in drug discovery because benzimidazoles exhibited enormous significance. So attempts have been made to create repository of molecules and evaluate them for prospective inherent activity. They are extremely effective both with respect to their inhibitory activity and favorable selectivity ratio. CONCLUSION: Benzimidazole is most promising category of bioactive heterocyclic compound that exhibit a wide variety of biological activities in medicinal field. The present review only focus on antimicrobial activity of reported benzimidazole derivatives may serve as valuable source of information for researchers who wish to synthesize new molecules of benzimidazole nucleus which have immense potential to be investigated for newer therapeutic possibilities.

Design, synthesis and biological profile of heterocyclic benzimidazole analogues as prospective antimicrobial and antiproliferative agents.

BACKGROUND: Nitrogen containing heterocycles are widely used and investigated by pharmaceutical industry, as they are important in discovery and designing of new drug molecules. Drugs with a benzimidazole nucleus possess exclusive structural features and electron-rich atmosphere, which enable them to bind to a number of biologically important targets and result in a wide range of activities. This has served as the basis of the present study whereby new scaffolds with benzimidazole moiety were designed and synthesized. METHODS: The structures of synthesized compounds were confirmed by physicochemical and spectral means. The synthesized compounds were screened for their antimicrobial and antiproliferative activities by tube dilution and Sulforhodamine B (SRB) assays, respectively. RESULTS AND CONCLUSION: The in vitro biological screening results revealed that compound Z24 exhibited promising antimicrobial and anticancer activities which are comparable to standards.

Benzimidazole scaffolds as promising antiproliferative agents: a review.

Cancer is one of the most serious medical problem and second leading cause of death in the world, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth. The benzimidazole is a heterocyclic moiety found in extensive number of natural and biological active molecules. Benzimidazole derivatives might be considered as auxiliary isosters of nucleotides having attached heterocyclic cores in their structures, cooperate effortlessly with biopolymers and have potential action for chemotherapeutic applications. Benzimidazole and its derivatives displayed a wide range of biological activity because of its structural similarity with the naturally occurring nucleotides. Benzimidazole has established huge alertness in current time and is extremely significant heterocyclic pharmacophore in recent drug innovation and medicinal chemistry. The present review summarizes the chemistry of various substituted benzimidazole derivatives with their antiproliferative significance towards the various cancer cell lines such as HCT116, MCF7, HeLa, HepG2, A549 and A431.

In-silico molecular design of heterocyclic benzimidazole scaffolds as prospective anticancer agents.

Benzimidazole is a valuable pharmacophore in the field of medicinal chemistry and exhibit wide spectrum of biological activity. Molecular docking technique is routinely used in modern drug discovery for understanding the drug-receptor interaction. The selected data set of synthesized benzimidazole compounds was evaluated for its in vitro anticancer activity against cancer cell lines (HCT116 and MCF7) by sulforhodamine B (SRB) assay. Further, molecular docking study of data set was carried out by Schrodinger-Maestro v11.5 using CDK-8 (PDB code: 5FGK) and ER-alpha (PDB code: 3ERT) as possible target for anticancer activity. Molecular docking results demonstrated that compounds 12, 16, N9, W20 and Z24 displayed good docking score with better interaction within crucial amino acids and corelate to their anticancer results. ADME results indicated that compounds 16, N9 and W20 have significant results within the close agreement of the Lipinski's rule of five and Qikprop rule within the range and these compounds may be taken as lead molecules for the discovery of new anticancer agents.

Pharmacological significance of heterocyclic 1H-benzimidazole scaffolds: a review.

Heterocyclic compounds are inevitable in a numerous part of life sciences. These molecules perform various noteworthy functions in nature, medication and innovation. Nitrogen-containing heterocycles exceptionally azoles family are the matter of interest in synthesis attributable to the way that they happen pervasively in pharmacologically dynamic natural products, multipurpose arranged useful materials also profoundly powerful pharmaceuticals and agrochemicals. Benzimidazole moiety is the key building block for several heterocyclic scaffolds that play central role in the biologically functioning of essential molecules. They are considered as promising class of bioactive scaffolds encompassing diverse varieties of activities like antiprotozoal, antihelminthic, antimalarial, antiviral, anti-inflammatory, antimicrobial, anti-mycobacterial and antiparasitic. Therefore in the present review we tried to compile the various pharmacological activities of different derivatives of heterocyclic benzimidazole moiety.

2-Mercaptobenzimidazole Schiff Bases: Design, Synthesis, Antimicrobial Studies and Anticancer Activity on HCT-116 Cell Line.

BACKGROUND: Increased rate of mortality due to the development of resistance to currently available antimicrobial and anticancer agents initiated the need to develop new chemical entities for the treatment of microbial infections and cancer. OBJECTIVE: The present study was aimed to synthesize and evaluate antimicrobial and anticancer activities of Schiff bases of 2-mercaptobenzimidazole. METHODS: The Schiff bases of 2-mercaptobenzimidazole were synthesized from 4-(2-(1H-benzo[d]- imidazol-2-ylthio)acetamido)benzohydrazide. The synthesized compounds were evaluated for antimicrobial and anticancer activities by tube dilution method and Sulforhodamine-B (SRB) assay, respectively. RESULTS: Compounds 8 (MICpa, an = 2.41, 1.20 µM/ml), 10 (MICse, sa = 2.50 µM/ml), 20 (MICec = 2.34 µM/ml) and 25 (MICca = 1.46 µM/ml) showed significant antimicrobial activity against tested bacterial and fungal strains and compounds 20 (IC50 = 8 µg/ml) and 23 (IC50 = 7 µg/ml) exhibited significant anticancer activity. CONCLUSION: In general, the synthesized derivatives exhibited moderate antimicrobial and anticancer activities. Compounds 8 and 25 having high antifungal potential among the synthesized compounds may be taken as lead molecules for the development of novel antifungal agents.

Design, synthesis and therapeutic potential of 3-(2-(1H-benzo[d]imidazol-2-ylthio)acetamido)-N-(substituted phenyl)benzamide analogues.

BACKGROUND: The emergence of bacterial resistance is a major public health problem. It is essential to develop and synthesize new therapeutic agents with better activity. The mode of actions of certain newly developed antimicrobial agents, however, exhibited very limited effect in treating life threatening systemic infections. Therefore, the advancement of multi-potent and efficient antimicrobial agents is crucial to overcome the increased multi-drug resistance of bacteria and fungi. Cancer, which remains as one of the primary causes of deaths and is commonly treated by chemotherapeutic agents, is also in need of novel and efficacious agents to treat resistant cases. As such, a sequence of novel substituted benzamides was designed, synthesized and evaluated for their antimicrobial and anticancer activities. METHODOLOGY: All synthesized compounds were characterized by IR, NMR, Mass and elemental analysis followed by in vitro antimicrobial studies against Gram-positive (Staphylococcus aureus), Gram-negative (Salmonella typhi and Klebsiella pneumoniae) bacterial and fungal (Candida albicans and Aspergillus niger) strains by the tube dilution method. The in vitro anticancer evaluation was carried out against the human colorectal carcinoma cell line (HCT116), using the Sulforhodamine B assay. RESULTS, DISCUSSION AND CONCLUSION: Compound W6 (MICsa, st, kp = 5.19 µM) emerged as a significant antibacterial agent against all tested bacterial strains i.e. Gram-positive (S. aureus), Gram-negative (S. typhi, K. pneumoniae) while compound W1 (MICca, an = 5.08 µM) was most potent against fungal strains (A. niger and C. albicans) and comparable to fluconazole (MIC = 8.16 µM). The anticancer screening demonstrated that compound W17 (IC50 = 4.12 µM) was most potent amongst the synthesized  compounds and also more potent than the standard drug 5-FU (IC50 = 7.69 µM).

Synthesis, SAR and in vitro therapeutic potentials of thiazolidine-2,4-diones.

BACKGROUND: Thiazolidinedione is a pentacyclic moiety having five membered unsaturated ring system composed with carbon, oxygen, nitrogen and sulfur molecules at 1 and 3 position of the thiazole ring and widely found throughout nature in various form. They favourably alter concentration of the hormones secreted by adipocytes, particularly adiponectin. They also increase total body fat and have mixed effects on circulating lipids. Thiazolidinedione nucleus is present in numerous biological moieties and has different pharmacological activities likes, e.g. antimalarial, antimicrobial, antimycobacterial, anticonvulsant, antiviral, anticancer, anti-inflammatory, antioxidant, anti-HIV (human immunodeficiency virus) and antituberculosis. RESULTS AND DISCUSSION: The synthesized compounds were screened for their in vitro antimicrobial potential against Gram (positive and negative) bacterial and fungal strains by tube dilution technique. In this series, compound 10 exhibited significant antimicrobial activity against B. subtilis and S. aureus with MIC = 4.2 × 10-2 µM/ml, compound 15 showed significant activity against K. pneumonia with MIC = 2.60 × 10-2 µM/ml and compound 4 displayed potent antibacterial activity against E. coli with MIC = 4.5 × 10-2 µM/ml. Compound 10 had most potent antifungal activity against C. albicans and A. niger with MIC = 4.2 × 10-2 µM/ml. Compounds 12 and 15 were found as most active antidiabetic agents having IC50 = 27.63 µg/ml and 22.35 µg/ml, respectively, using DPPH assay. Antioxidant activity results indicated that compounds 3 and 9 displayed good antioxidant agent with IC50 = 29.04 µg/ml and 27.66 µg/ml respectively, using α amylase assay. CONCLUSION: All the synthesized derivatives exhibited good antimicrobial, antidiabetic and antioxidant activities using specific methods then compared with mentioned standard drugs. Especially, compounds 3, 4, 9, 10, 12 and 15 displayed highest activity. Structure activity relationship demonstrated that presence of electron withdrawing group (o-NO2, p-Cl, p-Br) enhanced the antibacterial activity against E. coli as well as increased the antioxidant activity while the presence of electron releasing group (o/p-OCH3, 3,4,5-trimethoxy) enhanced the antibacterial activity against S. aureus, B. subtilis, S. typhi, K. pneumonia, C. albicans and A. niger as well as the antidiabetic activity.

Benzoxazole derivatives: design, synthesis and biological evaluation.

BACKGROUND: A new series of benzoxazole analogues was synthesized and checked for their in vitro antibacterial, antifungal and anticancer activities. RESULTS AND DISCUSSION: The synthesized benzoxazole compounds were confirmed by IR, 1H/13C-NMR, mass and screened for their in vitro antimicrobial activity against Gram-positive bacterium: Bacillus subtilis, four Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi and two fungal strains: Candida albicans and Aspergillus niger using tube dilution technique and minimum inhibitory concentration (MIC) was noted in µM and compared to ofloxacin and fluconazole. Human colorectal carcinoma (HCT116) cancer cell line was used for the determination of in vitro anticancer activity (IC50 value) by Sulforhodamine B assay using 5-fluorouracil as standard drug. CONCLUSION: The performed study indicated that the compounds 1, 10, 13, 16, 19, 20 and 24 had highest antimicrobial activity with MIC values comparable to ofloxacin and fluconazole and compounds 4, 6, 25 and 26 had best anticancer activity in comparison to 5-fluorouracil.

Biological potential of thiazolidinedione derivatives of synthetic origin.

Thiazolidinediones are sulfur containing pentacyclic compounds that are widely found throughout nature in various forms. Thiazolidinedione nucleus is present in numerous biological compounds, e.g., anti-malarial, antimicrobial, anti-mycobacterium, anticonvulsant, antiviral, anticancer, anti-inflammatory, antioxidant, anti-HIV (human immunodeficiency virus) and antitubercular agent. However, owing to the swift development of new molecules containing this nucleus, many research reports have been generated in a brief span of time. Therefore seems to be a requirement to collect recent information in order to understand the current status of the thiazolidinedione nucleus in medicinal chemistry research, focusing in particular on the numerous attempts to synthesize and investigate new structural prototypes with more effective antidiabetic, antimicrobial, antioxidant, anti-inflammatory, anticancer and antitubercular activity.