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Heterocycles by far are the largest classical divisions of organic chemistry and are of immerse importance biologically and industrially. The majority of pharmaceuticals and biologically active agrochemicals are heterocycle while countless additives and modifiers used in industrial application ranging for cosmetics, reprography, information storage and plastics are heterocycle in nature. One striking structural feature inherent to heterocycles, which continue to be exploited is their ability to manifest substituent's around a core scaffold i.e. benzimidazole.
Benzimidazole is important heterocyclic compound formed by the fusion of benzene ring with imidazole ring containing nitrogen, oxygen,sulphur and its derivatives are of broad interest since their biological activity and clinical applications.
Benzimidazole and its derivatives are most extensively studied class of bioactive molecules. Their importance is due to their versatile application in the field of drugs and pharmaceuticals as well as in chemical systems1. Thiabendazole 1, which is a benzimidazole analogue, is mainly used as antihelmintic5. They exhibit significant activity against several viruses including RNA2, herpes3, and HIV4. Moreover, some benzimidazole derivatives have been demonstrated to be potent antimicrobial6 and topoisomerase-1 inhibitors7, anti hepatitis-C virus agents8 and anticancer agents9.
During the last few decades, a considerable attention has been devoted to the synthesis of 1, 3, 4-thiadiazole, 1, 2, 4-triazole and 1, 3, 4-oxadiazole derivatives. 1, 3, 4-thiadiazole derivatives exhibit diverse pharmacological activities possibly due to presence of N=C=S10 moiety. Moreover, compounds with thiadiazole ring have been produced as anticonvulsant11, antibacterial12, anti-inflammatory13, fungicidal14 and anticancer agents15. Acetazolamide 2 and methazolamide 3 bearing thiadiazole moiety are commonly used as diuretics5.
Triazoles and in particular 1, 2, 4-triazole nucleus have been incorporated into a wide variety of therapeutically interesting candidates including antiviral16,
anticancer17, anticonvulsant18, anti-inflammatory agents19 and antimicrobial20 agents. Their antifungal activity is also documented. If Amphotericin-B is the most common drug used against systemic mycoses despite its toxic effect on humans, newer class of drugs such as fluconazole and itraconazole are used as systemic antifungal agents actually employed in patients with impaired immunity such as those who have AIDS or are neuropenic as a result of cancer therapy. Ribovirin 4, which is a triazole derivative, has antiviral activity5.
Nefazodone 5 is commonly used as antidepressant5.
1, 3, 4-Oxadiazoles are a class of heterocycles which have attracted significant interest in medicine, pesticide chemistry and material science. They are of significant interest in medicinal chemistry in a number of biological targets including, anti-inflammatory21, and human Î²-tryptase inhibitors22, and anticonvulsant23, antibacterial and antifungal agents24.
In recent years, various antitumor drugs have been developed for the treatment of cancer. Among these, compounds incorporating Schiff base structure were synthesized as antitumor25 and antimicrobial26 agents.
RATIONAL DRUG DESIGN
Modern drug discovery is a multidisciplinary approach wherein drugs are designed and /or discovered .The research and development expenditure bring on oneself a new chemical entity to the end of phase I efficiency of transforming phase III clinical trials is estimated to be around $ 1,3billion today in the US .The major contribution to this cost increase is the decrease in efficiency of transforming lead preclinical candidates from 75% to 50% and the rate of retrogression of compound from phase 2 phase 3 clinical trials from 50%to 30%. Despite advances in technology and understanding of biology systems, drug discovery is still a long process ( ï€› 15 years) with low rates of new discoveries. This scenario demands alternate techniques that reduce both the cost and the time period involved simultaneously increase the success rate.
Rational drug design (RDD)
Focus into the history drugs reveals that many early discoveries in the pharmaceutical industry were serendipitous; they fail to explain why a compound is active or inactive how it may be amended. The advent of new knowledge of physiological mechanisms has made it possible new chemical entities. The concept of Rational drug design could be traced to the findings of Paul Ehrlich (chemoreceptor) and Emil Fischer (lock and key model) in 1872 and 1894 respectively . To cause to move forward in molecular biology, protein crystallography and computational chemistry since the 1980s have greatly aided the RDD epitomes. The advent development of combinatorial chemistry and high throughput screening (HTS) in the 1990s led to a paradigms shift in drug
research. Combinatorial chemistry uncorked the chemical bottleneck in drug research shifting the question in lead optimization from "what can we make" to "which should we make"  contemporarily, HTS makes it possible to screen huge libraries of molecules within a short time span,. Despite that, initial euphoria that designated these techniques as universal lead generators subsided as a result of the considerable costs involved and disappointingly low hit rates . Lessons learnt from these strategies seeks complete shift of drug research paradigms from an empirical science to structure based analysis of macromolecule- ligand interactions fig 1 shows a flow chart that describes different approaches that enable RDD to evolve new NCE's with greater biological activity.
Figure 1.Different approaches of rational drug design 
Role of computer aided molecular design in drug discovery
It was realized in the 1960s, that computer based methods can be of help in the discovery of new leads and can potentially eliminate chemical synthesis and screening of many irrelevant compounds. An ideal computational method for lead discovery should be able to generate structurally diverse leads rapidly and should give estimate of binding affinities that would correlate with experimental values. Generation of chemical diversity in silico, is easily achieved from large database of compounds, or they can be "grown" computationally by joining molecular fragments. From another point of view, accurate prediction of binding affinities has been a more difficult task . Because of the multitude of energetic and entropic factors involved, the thermodynamics of binding cannot be analytically modeled without first simplifying the problem . Computational methods that attempt to design leads very in the nature and in the degree of the simplifying assumptions they use.
Approaches to RDD
Rational drug discovery can be divided into two broad categories: analog based study and structure based study based on the availability of three dimensional structure of the target.
Analog based studies
Analog based studies gather information from already existing drugs/ligands that are active against biological molecule (protein or DNA/RNA) of interest. Based on this information a set of rules are framed to either design a new ligand or modify an existing ligand in order to enhance biological activity.
Quantitative structure activity relationship (QSAR)
QSAR is the most widely used analog based methods. It aspires correlating structural features of a series of known compounds with their biological activities. From these correlations empirical equations are derived and subsequently used to guide the design of new leads. Early QSAR methods related biological activity to the presence of functional groups in series of structurally related compounds in the training set (Hansch analysis) .more recently, three dimensional QSAR methods have been developed . Although QSAR models reproduce binding affinities of ligands more accurately than other methods they have three major short comings.(i)sufficient number of ligands active against target of interest should be available to develop structure activity relationships.(ii) the equations that are parameterized for one target do not apply to another;and(iii) are of limited use in understanding the nature of protein -ligand interactions and thermodynamics of binding.
Pharmacophore is one another analog based method. The word Pharmacophore was coined by paul enrich in the early 1900s referring to a molecular frame work that carries the essential features responsible for a drug's biological activity . Later in 1977 Peter Gund redefined it as "a set of structural features in a molecule that is recognized at a receptor site and is responsible for those molecules's biological activity". Pharmacophore models are constructed based on molecules of known biological activity and are refined as more data are acquired in an iterative process. Alternatively, a Pharmacophore can also be generated from the receptor structure.
One step ahead, the dynamic pharmacophore model based on molecular dynamics trajectories takes care of the binding site dynamics . These models can be used for
optimizing known ligands or for screening databases to find potential novel leads suitable for further development .
Structure Based Studies
Structure based approaches, based on the three-dimensional structure of the target overcome many of the limitations of analog based studies. These methods help to develop a general theretical description of the protein -ligand interactions that would enable and a prior design of new leads for a particurar biological target . The first success story in structure based design is the antihypertensive drug captopril, an inhibitor of angiotensin converting enzyme (ACE) .Table 1 lists other examples of drugs derived from structure based approaches. Different approaches used for the structure based design are as follows.
Carbonic Anhydrase II
5-Hydroxy Tryptamine 1B
Objectives and plan of the present study:
The main objective of the present study is:
To synthesize the title compounds by simple methods.
To purify the final compounds by recrystallization and column chromatographic methods.
To characterize the synthesized compounds by physical and spectral methods
To evaluate the title compounds for antibacterial, antifungal activity by Serial dilution method and Cup-plate method respectively and evaluation of anti-inflammatory activity by Carrageenan induced rat paw edema method. and analgesic activity by writhing test and Tail clip method Writhing test using acetic acid.
Rational design of the title compounds: docking and drug likeness