checkpoint control br Experimental br Biological evaluation

Experimental
Biological evaluation
Conflict of interest
Acknowledgement
Introduction Malaria is a mosquito born disease caused by a single celled organism known as protozoa. Among the five types of malaria, the disease caused by Plasmodium falciparum is the most common and virulent. Although malaria is less common in the developed countries, yet it is a life threatening infectious disease in the developing Asian and African countries. While there are numbers of antimalarial drugs available, today an emergency occurred in the area of antimalarial drug search because of resistance occurred by the parasites against the available drugs [1,2]. Resistance to antimalarial drugs has been reported for only two species of parasite among the five viz. P falciparum and p. vivax. Among the two species P. falciparum acquired resistance to almost all the antimalarial drugs available, however the extent of resistance varies from drug to drug. The geographical distribution of resistant parasite depends upon the population movement from a resistant place to a nonresistant one. At present chloroquine resistant P.falciparum strain hass been reported everywhere throughout the world [3–6]. Molecules containing thiazole nucleus as a part are reported to have a diverse activities such as antimicrobial [7–9], anticonvulsant [10], analgesic and anti-inflammatory [11,12], antitubercular [13] and antican-cer [14–16]. It is been also reported that thiazole containing molecules are easily metabolised inside the body without the production of any toxic biproducts [17]. Molecules containing a thiazole ring attached with a substituted triazine nucleus were reported to have antimalarial activity as it can block DHFR (Dihydro Folate Reductase), which is a key enzyme responsible for metabolic activity in malarial parasites [18]. Rational drug design is also sometimes referred as drug design or rational design. In the era of modern drug design and discovery, computer aided drug design played a major rule. In checkpoint control to the traditional method of drug discovery, which relies on the trial and error testing rational drug design begins with a hypothesis that modulation in a specific target can give a desired pharmacological activity. With the advancement in the technology, it is now possible to simulate in vitro as well as in vivo condition within a computer using any sophisticated software. Accordingly molecules can be virtually screened for their activities as well as probable toxicities prior to a real laboratory work. This type of virtual screening enables the proper use of time and resources [19–22]. In the last two decades microwave assisted synthesis become very popular in pharmaceutical and academic areas because of its technology enabling a fast and steady chemical synthesis. Further advancement has been achieved in case of Enhanced Microwave Synthesis (EMS), where the reaction vessel is simultaneously cooled during the reaction time. Short reaction time and a wide range of reaction scope have enabled microwave assisted synthesis very popular among the researchers and industrial persons [23,24].
Materials and methods
Results and discussion The present study results in a systematic and rational plan of work that was carried out in order to overcome the different problems of the classical approach of drug discovery. Among the 60 different molecules designed, 10 were selected based on their affinity towards the target protein. Though there are some molecules among the selected, which were found to bind at the active site with different binding modes as that of 66B and 79B, they were selected for the study as because they were found to bind with other important amino acids of the same active site. Among the ten synthesized molecules, three molecules exhibited good result with wild type Plasmodium falciparum starin (3D7). Molecules found to show good inhibiting activity on the growth of 3D7 strain were further tested with RKL2 strain which is a chloroquine mutant strain. IC50 value of molecule 66B suggests that can be further studied and modified to have new active antimalarial antifolate.