Malaria, an illness spread by mosquitoes, is a persistent issue in worldwide public health. It leads to the death of millions of people worldwide, especially in tropical regions of Africa and South Asia (Talapko, et al., 2019). Based on the World Health Organization's (WHO) World Malaria Report 2022, the worldwide incidence of malaria in the year 2021 was estimated to be around 247 million cases, with an estimated 619,000 deaths (WHO, 2022). The current antimalarial medications have consistently demonstrated efficacy in controlling malaria, despite the availability of prophylactic vaccines (Brown, 2015). Chloroquine (CQ), a pharmaceutical compound that has been widely preferred since the 1940s, has numerous noteworthy advantages including substantial efficacy, a positive safety record, and cost-effectiveness. However, the detection of chloroquine (CQ) resistance was first seen in the late 1950s in the vicinity of the Thailand-Cambodia border, as well as the Panama-Colombia border. Following this, the previously described phenomena expanded its influence to Burma during the 1960s, subsequently spreading to central India in the 1970s, and eventually reaching East Africa in 1978. As a result, the effectiveness of cultural intelligence (CQ) in East Africa saw a progressive decline (Parker, et al., 2015). The period marked by the economically viable administration of chloroquine (CQ) for the treatment of malaria was nearing its conclusion. During the 1980s, Africa had a notable escalation in mortality rates associated with malaria, a phenomenon that can be traced to a considerable rise in resistance to chloroquine (CQ). According to Roux et al. (2021), the observed rise was found to be two to three times more than the values seen in earlier studies. As shown by Maiga et al. (2021), there has been a significant shift in the major treatment strategy in Southeast Asia and South America, with a switch from Chloroquine (CQ) to Artemisinin-based combination therapy (ACT). The region of Southeast Asia has experienced a recent development of resistance to Artemisinin-based combination treatments (ACT), leading to adjustments in the approaches utilized for the management and elimination of malaria (Siddiqui, et al., 2021). As the resistance to ACT spreads to more malaria-endemic regions, the probability of a global health disaster increases (Arya et al., 2021). In the past two decades, a small number of antimalarial medications have been developed (Belete, 2020), thus there is an urgent need for the discovery and development of novel antimalarial agents. According to Manohar et al. (2013) and Kumar et al. (2014), the chemical 1,3,5-triazine is a valuable precursor for the production of antimalarial medications. The convenience of its synthetic accessibility is principally attributable to the utilization of cyanuric chloride, a readily available and cost-effective starting material (Thurston et al., 1951; Haval, 2006; Hamon et al., 2009). The scholarly literature extensively acknowledges the antimalarial properties exhibited by compounds derived from 1,3,5-triazines may be attributed to their capacity to create robust hydrogen bonds, participate in electrostatic and charge-transfer interactions, and engage in aromatic-stacking interactions with the Pf-DHFR-TS receptor (Adhikari et al., 2023; Saha et al., 2023). In our earlier studies, we have developed various substituted 1,3,5-triazine as effective lead against various disease (Bhat et al., 2013; Bhat et al., 2016; Singh et al., 2012; Singh et al., 2012).

In addition to this, in 2021, we have synthesized various PABA-1,3,5-triazine compounds, and among these compounds, compound 4c11, exhibited an IC50 value of 14.90 μg/mL against the CQ-sensitive 3D-7 strain. In the next instance, we have showed the development of hybrid dimethoxy phenyl substituted pyrazole-1,3,5-triazine derivatives, where compound 7e exhibited an IC50 value of 53.85 μg/mL against the CQ-sensitive 3D-7 strain, as depicted in Figure 1 (Gogoi et al., 2021). Therefore, based on the previous results, we have designed the novel series of pyrazole-1,3,5-triazine derivatives with trimethoxy phenyl substitution using the docking, and subsequently tested for antimalarial activity.