Revealing analgesic and anxiolytic potentials of synthetic benzimidazole analogues: An in-vivo and in-silico study.

Certain drugs have potential to affect and alter individual's behavior. On the other hand, pain is a complex phenomenon with various treatment options; analgesic medicines are the primary source. Therefore, this study was based on examining some of the benzimidazole analogues for their analgesic as well as behavioral potential following Tail immersion test and Open field test respectively. In addition, molecular docking was performed to find the interaction of these compounds with the active site using AutoDock Vina which was further visualized through Discovery Studio Visualizer. It was seen that the cyano-methyl benzimidazole derivatives (CMB1-CMB3) showed relief in pain as compared to benzimidazole derivatives (BI1-BI3), CMB2 demonstrated highly potent analgesic effect. Likewise, all structures except BI1 displayed increase locomotion during open field test and can be offered as anxiolytic compounds. Almost all derivatives showed improve binding energies for the tested proteins where the high analgesic action of CMB2 might be correlated to its high binding affinity and interaction at µOR. It was also noticed that all structures except BI showed possible binding interaction with GABAA receptor and hence possessed anxiolytic like potential. Thus, this study offered benzimidazole analogues for further drug development of analgesic and anxiolytic like compounds.

Determination of ionization constant and drug-likeness prediction of synthetic isoniazid derivatives.

Determination of ionization constant, commonly termed pKa is of prime interest in a wide range of pharmaceutical Research fields. The pKa of a compound is critical as it influences on its physicochemical parameters in biological and environmental systems. The study of pKa is also essential not only for the formulation of drugs and optimization of a variety of novel analytical methods, establishing new pharmaceutical dosage forms yet the exploration of the mechanism of action of drugs. In this research work, we have determined pKa values of isoniazid (INH) derivatives; N'-[(4-methyl benzoyl)] pyridine-4-carbohydrazide (I) and [2-oxo-2-(4-phenyl phenyl) ethyl] (pyridine-4-yl formamido) azanium bromide (II) through UV- spectrophotometry, a method is known for the accuracy and precision of results. These two compounds (I and II) were synthetically prepared in our lab by derivatizing INH and reported by Naeem et al in the year 2014. The mean pKa values for compounds I and II were experimentally determined as 7.37 and 3.76 respectively. The study is helpful in understanding the physicochemical behavior of these compounds in a biological system. Different pharmacokinetic parameters were also predicted using online web tools which ensured significant drug-likeness for both compounds.

In-silico determination of pKa and logp values of some isoniazid synthetic analogues using Marvin software.

Among the physicochemical properties, pKa and LogP values help us in studying drug parameters like ADME and could be predicted to some extent. With this view, here we wish to predict these two properties of our previously synthesized biologically active derivatives of isoniazid using on-line available program Marvin, a Java-based chemical software application frequently used for chemical modeling. According to Marvin, pKa values predicted 99.99% unionized states of INH and some derivatives at physiological pH 7.4. Marvin calculated LogP values estimated good oral absorption for all the synthesized compounds. Therefore it can be said that the findings of the study emerged in an ideal region that permits the formulation of these derivatives. Since this was just a theoretical study, it demands more experimentation to determine accurate situation.

Synthesis, characterization and SAR of novel Bezimidazole derivatives as Nematicidal agents.

Six novel analogues were prepared by reacting benzimidazole molecules (BM and CMB) propiophenone and benzoyl chlorides respectively. The structures of newly synthesized compounds were determined with the help of spectroscopic techniques. The compounds were subjected to in-vitro screening for their activity against nematodes. It was observed that the benzimidazole (BM) derivatives possessed more nematicidal activity as compared to that of cyanomethyl-benzimidazole (CMB) for Meloidogyne incognita. Among them, the propiophenone substituted benzimidazole derivative B3 was found to be the most active compound and can be further studied as lead molecule for development of anthelmintic drugs.

Pharmacophoric screening of newly synthesized isoniazid derivatives and their antimycobacterial activity.

Mycobacterium tuberculosis is clinically recognized as a causative agent of Tuberculosis. Keeping in view, this study was endeavored to screen our previously synthesized seventeen INH analogues for their antimycobacterial potential using proportion method. During this process, INH and all the seventeen compounds were examined at different concentrations of 0.05, 0.1 and 0.2µg/mL which were prepared using Lowenstein-Jensen (LJ) base. For drug susceptibility test, three Mycobacterial strains ATCC H37Rv, known INH-sensitive and INH-resistant strains were selected, sub-cultured on LJ Medium and serial diluted to achieve 1:10, 1:100, 1:1000 and 1:10000 from calibrated bacterial suspension Mcfarland No. 1. Dilutions of 1:100 and 1:10000 were added to drug free medium and 1:100 bacterial suspension was added to each of the test concentrations and finally incubated for 4-6 weeks at 37°C. It was observed that only compounds II and XI were active against MTb. Compounds III, IX and X also showed activity but were less potent. Ligand Scout 3.02[il_10] was used to perform pharmacophore-based screening where important pharmacophoric features were identified in the structures of these compounds which could be related to their observed antimycobacterial activity.

Cytotoxic and acute toxicity studies of isoniazid derivatives.

Cancer is ultimately the result of cells that hysterically grow and do not die. Cells can experience uncontrolled growth if there are mutations to DNA, and therefore, alterations to the genes involved in cell division. Cancer occurs when a cell's gene mutations make the cell unable to correct DNA damage and is unable to destroy itself. There are over 100 different types of cancer each classified by the type of initially affected cell. Isoniazid, a well-known antitubercular agent has been reported to exhibit some cytotoxic activity. This finding prompt us to carry out this study where isoniazid and its sixteen derivatives were studied for any possible cytotoxic activity against Human astrocytoma SNB-19 cells, human Dukes' type C colorectal adenocarcinoma HCT-15 cells, human Dukes' type D colorectal adenocarcinoma COLO-205 cells, and human prostate adenocarcinoma (grade IV) PC-3 cells. Among the test compounds, SN-07 (a phenacyl derivative with para phenyl substitution) demonstrated slight cytotoxic effects on two types of human colorectal adenocarcinoma cells HCT-15 and COLO-205. Moreover, the acute toxicity of the compounds was also estimated in which some compounds were evaluated with more LD50 values than isoniazid.

Antimicrobial and antioxidant screening of N¢-substituted sulphonyl and benzoyl derivatives of 4-Pyridine carboxylic acid hydrazide.

In this research program, the antibacterial, antifungal and antioxidant activities of six N'-substituted sulfonyl and benzoyl derivatives of lead molecule PCH were reported. Out of these compounds, sulphonyl derivatives 2,3 and benzoyl derivative 5 showed moderate to good activity against different strains of gram-positive and gram-negative bacteria including B. cereus, B. subtilis, B. thruingiensis and S. pyogenes, S. fecalis and E. coli ATCC 8739. Moreover, upon antifungal screening, the compound, N¢-[(2,4,6-trimethylbenzene) sulfonyl]pyridine-4-carbohydrazide possessed good antifungal activity against Candida species, a causative agent of systemic fungal infections. Antioxidant study demonstrated more than 50% inhibition in DPPH assay for sulphonyl derivative 2 indicating its potential as antioxidant while the other derivatives expressed low level of radical scavenging property.

Antimalarial and insecticidal activities of newly synthesized derivatives of Benzimidazole.

The bioactive benzimidazole and corresponding substituted phenacyl halides has been synthesized (11) new derivatives out of three compounds 8, 10 and 11 were found to inhibit the Plasmodium falciparum moderately after 72 hours of incubation hence acting as antimalarial agents. While these derivatives were exhibited negligible insecticidal activity too when analyzed by impregnated filter paper method.

Synthesis of novel derivatives of 4-pyridine carboxylic acid hydrazide and their activity on central nervous system.

Six novel derivatives (2-7) of 4-Pyridine carboxylic acid hydrazide (PCH) were synthesized by treating this lead molecule with substituted arylsulphonyl and benzoyl chlorides. The molecular structures of the newly derived products were characterized by the help of UV Visible, IR, FAB, 1HNMR spectroscopy and CHN analysis. During the preliminary pharmacological screening, it was observed that the synthesized compounds induced noticeable changes on motor activity of the animals. Interesting structure activity relationship was also observed among the synthesized molecules. Because of the interesting affect on motor activity, the newly synthesized derivatives can further be evaluated for their effects on CNS.

Determination of pKa values of new phenacyl-piperidine derivatives by potentiometric titration method in aqueous medium at room temperature (25±0.5oC).

Dissociation constant (pKa) of ten novel phenacyl derivatives of piperidine were determined by potentiometric titration method in aqueous medium at room temperature (25 ±0.5°C). The sample solutions were prepared in deionized water with ionic strength 0.01M and titrated with 0.1M NaOH solution. In addition, ΔG values were also calculated. Different prediction software programs were used to calculate pKa values too and compared to the experimentally observed pKa values. The experimental and theoretical values were found in close agreement. The results obtained in this research would help to predict the good absorption of the studied compounds and can be selected as lead molecules for the synthesis of CNS active agents because of their lipophilic nature especially compound VII.