Drug Discovery and Exploration of Heterocycles for the Development of Anti-HIV Agents.

It is a known fact that HIV infection remains a serious public health problem throughout the world, and the need to constantly develop new antiretroviral drugs to combat HIV emerges from the fact that repetitive mutations occurring in viral enzymes make this virus resistant to antiretroviral drugs. This resistance causes failure of treatment, and hence, for many years, extensive research has been to discover newer possibilities for fighting this disease at a molecular level, along with many long-standing and expensive clinical trials. Many scientific research programs have either been discarded or unsuccessful. However, the research has not stopped, and in the process, many heterocyclic scaffolds have been used to build up novel drug molecules to combat this disease. A literature survey reveals that many heterocycles have been explored and were found to be very useful in treating different types of viral infections. This concise and rigorous literature explains the journey and highlights the various strategies to develop new anti-HIV drug candidates.

Drug Repositioning: A Unique Approach to Refurbish Drug Discovery.

For a decade, it has been observed that there is a remarkable decrease in the quantum of novel clinically approved drugs, in spite of modernization in the research and development process. We have highlighted repositioning of drugs as a methodology that has found new therapeutic implications for clinically approved drugs but with different indications. This can be considered as an upbringing strategy to deliver timely and cost-effective solutions, which still need exploration for getting over the shortage of novel drugs reaching the market. This review focuses on an activity-based drug repositioning approach, which is used to explore new uses of known drugs that are already approved for specific indications and are now being used for other indications on the basis that a single drug interacts with multiple targets. It also includes current research trends related to drug repositioning, which depends on strong knowledge of medicinal chemistry and involves elucidation of mechanisms of action and validation of novel targets. The review highlights the importance of computational tools and databases of various forms for drug repositioning purposes, which have enhanced the ability to pose reasonable and testable hypotheses. The critical nature of this aspect is obvious in cases where data gathered from in vitro, or animal models do not confirm in subsequent clinical trials. Hence, considering the positive outcomes of drug repositioning, it can be surmised that this approach can serve as a promising one that can develop into a robust drug discovery strategy.

The Design, Synthesis, and Evaluation of Diaminopimelic Acid Derivatives as Potential dapF Inhibitors Preventing Lysine Biosynthesis for Antibacterial Activity.

We created thiazole and oxazole analogues of diaminopimelic acid (DAP) by replacing its carboxyl groups and substituting sulphur for the central carbon atom. Toxicity, ADME, molecular docking, and in vitro antimicrobial studies of the synthesized compounds were carried out. These compounds displayed significant antibacterial efficacy, with MICs of 70-80 µg/mL against all tested bacteria. Comparative values of the MIC, MBC, and ZOI of the synthesized compound were noticed when compared with ciprofloxacin. At 200 µg/mL, thio-DAP (1) had a ZOI of 22.67 ± 0.58, while ciprofloxacin had a ZOI of 23.67 ± 0.58. To synthesize thio-DAP (1) and oxa-DAP (2), l-cysteine was used as a precursor for the L-stereocenter (l-cysteine), which is recognized by the dapF enzyme's active site and selectively binds to the ligand's L-stereocenter. Docking studies of these compounds were carried out using the programme version 11.5 Schrodinger to reveal the hydrophobic and hydrophilic properties of these complexes. The docking scores of compounds one and two were -9.823 and -10.098 kcal/mol, respectively, as compared with LL-DAP (-9.426 kcal/mol.). This suggests that compounds one and two interact more precisely with dapF than LL-DAP. Chemicals one and two were synthesized via the SBDD (structure-based drug design) approach and these act as inhibitors of the dapF in the lysine pathway of bacterial cell wall synthesis.

Molecular Docking, G-QSAR Studies, Synthesis and Anticancer Screening of Some New 2-Phenazinamines as Bcr-Abl Tyrosine Kinase Inhibitors.

BACKGROUND: The computational studies on 2-phenazinamines with their protein targets have been carried out to design compounds with potential anticancer activity. This strategy of designing compounds possessing selectivity over specific tyrosine kinase has been achieved through G-QSAR and molecular docking studies. METHODS: The objective of this research has been to design newer 2-phenazinamine derivatives as Bcr-Abl tyrosine kinase inhibitors by G-QSAR, molecular docking studies followed by wet lab studies along with evaluation of their anticancer potential. Computational chemistry was done by using VLife MDS 4.3 and Autodock 4.2 followed by wet lab experiments for synthesizing 2- phenazinamine derivatives. The chemical structures of ligands in 2D were drawn by employing Chemdraw 2D Ultra 8.0 and were converted into 3D. These were optimised by using semiempirical method called MOPAC. The protein structure was retrieved from RCSC protein data bank as PDB file. The binding interactions of protein and ligands were done by using PYMOL. The molecular properties of the designed compounds were predicted in silico by using Osiris property explorer. Later, we synthesized novel 13 2-phenazinamine derivatives by treating parent compound with various aldehydes in the presence of dicyclohexylcarbodiimide (DCC) and urea to afford 2-(2-chlorophenyl)-3-(phenazin-2-yl) thiazolidin-4-one and another series of derivatives synthesized with different aldehydes in the presence of p-toluylsulphonic acid, diphydropyridine and benzene sulfonyl chloride to afford benzenesulfonyl-N-(2-chlorobenzyl)-phenazin-2-amine. All the derivatives were tested for invitro anticancer activity on K562 human chronic myelogenous leukemia cell line by employing MTT assay method. RESULTS: The developed G-QSAR models were found to be statistically significant with respect to training (r2=0.8074), cross-validation (q2=0.6521), and external validation (pred_r2=0.5892). The best developed G-QSAR model suggested that the XlogP values of phenazinamine derivatives were found to be highly influential in determining biological activity. The standard drug was found to exhibit binding energy - 6.79 kcal/mol and the derivatives 5b and 6c exhibited binding energy of - 7.46 and - 8.51; respectively. CONCLUSION: Compounds 5b, 6c were observed to possess good lipophilicity and were found to exhibit better activity than other compounds in the series, although less than standard doxorubicin. The synthesis of these 2-phenazinamine derivatives (5a-m) is reported to be obtained from 2,4- dinitrodiphenylamine by applying appropriate synthetic route. Compounds 5b and 6c showed better cytotoxic activity against K562 cancer cell line when compared to other compounds of the series, although less than standard doxorubicin.

Synthesis and Pharmacological Evaluation of Tetrazolobenzimidazoles as Novel Anti-inflammatory Agents.

BACKGROUND: Currently used anti-inflammatory drugs are associated with some severe side effects such as gastric irritation, which may range from simple discomfort to ulcer formation. Therefore, the development of potent anti-inflammatory drugs with fewer side effects is important. Benzimidazole, tetrazole and its various derivatives have been used in the synthesis of numerous heterocyclic compounds. In the past few decades, these compounds received much attention due to their diverse array of biological activities. As these heterocycles are known to possess anti-inflammatory activity individually, we thought it worthwhile to link these heterocycles, synthesize them and evaluate for possible changes in this anti-inflammatory activity. METHODS: Novel benzimidazole linked tetrazole compound 2-{[2-(1H-tetrazole-5-yl)ethyl] sulfanyl}-1,3-benzimidazole (3) was synthesized by cyclization of 3-(1,3-benzimidazol-2-ylsulfanyl) propanenitrile in presence of sodium azide. A series of tetrazolobenzimidazole derivatives (3a-h) were synthesized by the reaction of compound (3) with acid chlorides. All the synthesized compounds were subjected to structural elucidation by IR, 1H-NMR spectroscopy, Mass spectrometry and elemental analyses. The newly synthesized compounds were screened for anti-inflammatory activity by carrageenan-induced paw oedema method in albino rats. RESULTS: Compounds (3a, 3c, 3g) which contain acetyl, benzoyl and benzoyl moieties; respectively at N-1of tetrazole exhibited anti-inflammatory activities comparable with standard drug diclofenac. Other compounds exhibited anti-inflammatory activity less than the standard. The differences between control and treatment group were tested using one way ANOVA followed by Dunnett's test. A probability value less than 0.01 was considered to be statistically significant. The GraphPad Instat 3.0 version was used for statistical analysis. CONCLUSION: Synthesized compounds having anti-inflammatory activity better than standard were found to be 1-{5-[2-(benzimidazol-2-yl-sulfanyl)ethyl]-2H-tetrazol-2yl}methanone (3c) and 1-{5-[5-methoxy-2-(benzimidazol-2-yl-sulfanyl)ethyl]-2H-tetrazol-2yl}methanone (3g) and the compounds (3a, 3e, 3f) were found to exhibit anti-inflammatory activity comparable to that of standard. All the compounds were found to cause less gastric ulceration than the standard drug diclofenac.

Zinc-aceclofenac complex: synthesis, hydrolysis study and antiinflammatory studies.

Aceclofenac, a nonsteroidal anti-inflammatory drug, has a propensity to cause gastric ulcers, while zinc ions are known to possess anti-ulcer and anti-inflammatory activities. With a view to reduce the gastroenteropathies associated with aceclofenac, its zinc complex was prepared and characterized using spectroscopy and differential scanning calorimetry. In vitro hydrolysis study showed that zinc complex of aceclofenac is more stable in HCl buffer (pH 1.2) than in phosphate buffer (pH 7.4) indicating the stability of the complex in stomach. In silico testing of the aceclofenac and its complex using PASS (Prediction of activity spectra of substances) software revealed that the complex might possess antiinflammatory activity which was confirmed by carrageenan-induced rat paw edema test. It has been found that antiinflammatory activity of this complex is comparable with that of parent drug along with reduction in ulcer index. Thus, the use of complex is suggested to be more preferable than aceclofenac alone.