A Medicinal Active Moiety: 3,4,5-TRIMETHOXYBENZOIC ACID DERIVATIVES

The most fundamental goal of drug design is to predict the given molecule bind to target or not if yes then what are the forces of binding and how strongly it can bind. Molecular dynamics used to estimate the strength of inter-molecular interaction between the small molecules and the targe

  DRUG DISCOVERY CYCLE

Hansch in early 19 century introduced Quantative structure relationship. The data for the QSAR model development should be very accurate biological info. The equilibrium constant and rate constant are relative to free energy concerned (Martin 1999). 

 Parameters of QSAR- Electronic parameter-hammett constant (Hammett 1970)

 Hydrophobic parameter-Partition coefficent

 Steric parameter-Taft’s factor

DOCKING- is a computational tool to investigate the binding between the macromolecular target and potential ligand. Docking consists of an essential part of the structure based drug design. The fundamental of the aspects of the docking process is the scoring of protein and ligand interaction. Docking is actually an energy-optimization problem concerned with the search of the lowest free energy binding of a ligand within a protein binding site. Docking always requires two components characterized as searching and scoring (Kaldor 1997).

TYPES OF DRUG DESIGN- 1.LIGAND-BASED DRUG DESIGN                                                 2. STRUCTURE-BASED DRUG DESIGN

LIGAND BASED DRUG DESIGN

 STRUCTURE-BASED DRUG DESIGN

THREE STEPS OF MEDICINAL CHEMISTRY-

DISCOVERY STEP 

OPTIMIZATION STEP

DISCOVERY STEP

The antimicrobial agents are used for the treatment of infectious diseases successfully. The discovery and development of new antimicrobial agents are essential because accounted for multiplex classes of medicines that are used habitually to serve multifold diseases. Over the ages at hand has been an extension improvement of resistance in organisms that are characteristic pathogens in specimen (Narang and Sharma 2012). 

There are multiplications in number of statements of multi-drug resistance rod-shaped aerobic bacteria in the United States and over the world. Another holistic that cut down the effectiveness of treatment of these organisms is concurrence in finalization treatment regimens. Outstretched of treatment and antagonistic of the treatment furnish to the lack of concession (Fie, Je, Shin and Seo 2017). 

Microorganisms are persistently changing, ways to fight for one’s life, and customize to current situations. Meanwhile progression microorganism can spin to ghostly strain and pass from their host to human. Advancement of unfamiliar classes of drugs with fewer side effects and compressed lengths of treatment are key in lasting the battle against infectious diseases (Mandekar, Dadkar, Sheth 1969). 

On aromatic systems methoxy group have been extensively investigated for their biological activity. An example of methoxy group in aromatic system in Trimethoprim had been greatly used in combination with sulfamethoxazole and called as cotrimoxazole. This combination was formed to minimize the antibiotic resistance of sulfamethoxazole (Lin, Yu and Lateef 2009).

 It has a role as a plant metabolite (Vazakas and Doluisio, 1964). It is also known as Eudesmic acid / Gallic acid trimethyl ether. Eudesmic acid is isolated from eucalyptus oil.  These derivatives of benzoic acid possess various pharmacological activities and key intermediates, starting material for various heterocyclic active compound syntheses (kareem, 2016).

                                           3,4,5-Trimethoxy-benzoic acid

                                                                Hydrazone

 Hydrazones are a important class of organic chemistry that possess the structure R_(1 ) R_(2 ) C=NNH_(2.)The azomethine (HC=N) double bond today known as Schiff base was prepared first time by the chemist Hugo Schiff (Moffelt and Rabjohn, 1960). 

 The Schiff base resembles the aldhyes and ketones on oxygen replacing by –NNH functional group. Hydrazones are the universally passed down biological compounds. The various aromatic Schiff base utilised to calculate to the concentration of low molecular weight aldhydes or ketones. They act as intermediates in many reactions such as mannich reactions type, asymmetric syncyanation and allylation reactions (Ray 2008).

 The hydrazone based compounds possessed a huge advantage in the branch of medical biotechnology that the hydrazone-based bond stable at the neutral pH (blood pH) but at the acidic environment the hydrazone-based bond gets break by the lysosomes and the compound become free for its biological action (Wei 2010).

The hydrazone have the tautomeric ability this means keto-enol form. In the solid state the schiff base exists in the natural keto form but in the solution they exist in the keto-enol form or only in deprotonation enol form. The conjugation gets increased due to the transfer of hydrogen atom in the π-electronic configuration. 

Compounds are hand-me-down as colouring and dyes, stimulant, intermediates in Chemistry fusion of heterocyclic compounds. If the schiff base is derived with the various heterocyclic rings it found to be exhibit anticonvulsant, anticancer and anti-proliferative properties. Theshowed a wide range of organic action like anesthetic, anti-inflammatory, antifungal, antimicrobial and antipyretic properties (Liu & Wu, 2009).

The –NH hydrazo and carbonyl group possessed intra-molecular bonding in them which results of the presence of both hydrogen acceptor and donor in the Schiff base (Fei 2014). 

MECHANISM OF HYDRAZONE-

A lone pair of the extreme nitrogen atom is conjugated with C=N double bond. Hydrazones are nucleophilic due to two nitrogen atoms; on the other hand the amino type nitrogen is major susceptible one. The carbon atom of hydrazone possesses both electrophilic and nucleophilic nature. The hydrogen atom of the Schiff base is more potent than acidic ketones (Krishnan 1971).

It is relevant to figure that a few of hydrazones possibly retrieve like E/Z-geometeric isomers (the motif Z and E represents the Cis and Trans arrangement of the group attached to the hydrazone).The stereochemistry of the Hydrazone is favourable E (Tabin, Hegarty, & Scott, 1971).   

THE ACTIVE CENTRE OF HYDRAZONE

Heterocyclic compounds are the organic compounds that contain in addition to carbon, oxygen or sulphur as a part of the ring. They may be simple aromatic or non-aromatic rings (Ameya 2007).

These molecules are the blessing in the chemical and life world. The research in this world has become a journey of thousand miles. Vast variety of heterocyclic molecules tuned itself in the modern drug classes. For the numerous syntheses of heterocyclic compounds and these compounds are also found to be fruitful as intermediates (Mullican, Wilson, Conner, Kostlan, Schries and Dyer, 1993).

THIAZOLIDINONE-

Brown in 1961 examined the science of thiazolidinone. The thioether group and an amine group in the 1,3 positions of five-member saturated ring. The saturated form of thiazole with 4-position carbonyl called 4-thiazolidinone (Perez, Webster, Allen and Brown 2011). 

Change is feasible at 2,3 and 5 position. Diversified optical and geometrical isomers are correlated with plentiful pharmacological properties and the examples are given below of the biological activity (Kareem 2016). 

4-Thiazolidinone comprises – molecular weight-103.413, molecular formula-C_3 H_5NOS.

Physical properties-

 Description- Yellow crystal and odourless

 Melting point- 194 ̊C

  Density- 1.278 g/〖cm〗^3 

Antihistaminic agent                                                         Anti-inflammatory agent

Antibacterial activity of the most potent activity of 4-thiazolidinone ring. The N-3 and C-2 position on the 4-thiazolidinone highly shows the activity against the bacteria so this two are essential site for the new molecules to be derived. The active substance found in both nature and synthetic routes (Saeed 2007). 

It possesses some other fascinating activities that are given below in a diagram form figure-2.

BIOLOGICAL ACITIVES OF 4-THIAZOLIDINONE

The substituted thiazolidine moiety fascinated noticeable concern in the evolution of biological progressive compounds (Sharma, Samadhiya, Srivastava and Srivastava 2012). Heterocyclic compounds consisting of a five-membered C_3 NS ring and are a colorless liquid. Examples- pioglitazone and antibiotic penicillin. Thiazolidinone congeners act as a CNS active agents. 4-Thiazolidinones are more soluble in water without alkyl or aryl substituent’s and the use of compounds diminished due to the addition of subtituent which decreases the water solubility (Nirwan, Chahal and Kakkar 2018).

REACTIONS OF 4-THIAZOLIDINONE

 The 5-methylene carbon atom of 4-thiazolidinone is nucleophilic (Emsley, Feeney, Sutcliff and Pergamen 1965). These complexes showed numerous anticipating applications (Wong, Yaan, Liu and Liu 2015).

Taylor reported the characteristics bands in the infrared spectra. He described the benchmark for determining the Cis and Trans configuration.The carbonyl peak of 4-thiazolidinone commonly found in mid of 1760-1665〖cm〗^(-1) (Sucheta, Tahlan and Kumar 2010).