Malaria is a disease that has afflicted humanity for millennia. There were 247 million malaria cases in 84 malaria-endemic countries in 2021, compared to 245 million cases in 2020 and 63000 deaths between 2019 and 2021. Over the past two decades, the disease claimed more young lives (World malaria report, 2022). In WHO's eastern Mediterranean region, malaria deaths increased by 49% between 2016 and 2020, where 80% of the cases were due to Plasmodium falciparum (P. falciparum) (Phillips, 2001).

P. falciparum is humans' most virulent malaria-causing protozoal species, accounting for most malaria cases in Africa and Southeast Asia (Olliaro 2001). Development of resistance to the currently available antimalarial drugs, including pyrimethamine, halofantrine, mefloquine, and quinine, is a significant barrier in the decade-long attempt to reduce and eliminate the disease. As a result, novel antimalarial drugs with distinct chemical structures and modes of action are urgently needed (Warhurst, 1987, 1998).

The intense search for new effective antimalarial is in demand in this context. A study of the differences in the metabolic and biochemical aspects between parasite and host cells often shows a deliberate strategy for selective chemotherapy. Biochemical processes significant to the growth of parasites can be selectively inhibited without harming the host cell. Malarial parasite synthesizes folate factor de novo, and the importance of para-aminobenzoic acid (PABA) in the folate metabolic pathway of the malarial parasite was reported recently using PABA-dependent auxotrophic mutants (Sirawaraporn 1998, McConkey et al., 1994). PABA is a widely utilized amino acid in biochemistry and medicinal chemistry, with a wide range of commercial applications. It's been discovered that it's an essential ingredient for most human pathogens (Krátky et al., 2019).

Another pharmacophore is 1,3,5-triazine, and its derivatives were the focus of attention for antibacterial (Bhat et al., 2013; Singh et al., 2021), antimalarial (Agarwal et al., 2005; Sunduru et al., 2009; Gahtori et al., 2012), antiprotozoal (Baréa et al., 2018), antifungal (Singh et al., 2012), anticancer (Saczewski et al., 2006), antimycobacterial (Sunduru et al., 2010), and antiviral (Maarouf et al., 2011) biological activity. The combination of certain bioactive pharmacophores with 1,3,5 triazine has been discovered to have a significant impact on antimalarial activity, such as hybrid 4-aminoquinoline 1,3,5-triazine (Bhat et al., 2016), thiazole-1,3,5 triazine (Sahu et al., 2019), pyrazole-1,3,5 triazine (Gogoi et al., 2021), and pyrimidine-1,3,5 triazine derivatives (Kumar et al., 2014).

The nitrogen-containing triazine motif had become a ‘Masterkey,’ providing the foundation for designing biologically relevant molecules with broad applications in chemotherapy such as antiprotozoal, anticancer, anti-inflammatory, antiviral, etc. (Baréa et al., 2018; Saczewski et al., 2006; Maarouf et al., 2011). The investigation of 1,3,5-triazine as a promising scaffold for its diverse biological behavior revealed that substituting different groups on the 1,3,5-triazine ring confers other pharmacological activity (Singla et al., 2015). Significant antifolate antimalarials (pyrimethamine and cycloguanil) share the pharmacophore dihydro triazine, structurally similar to natural dihydrofolate and thus has a high drug-receptor binding affinity. The flexible side-chain of WR99210, an analog of cycloguanil found complexed with the structure of the quadruple mutant, avoided potential steric clashes, explaining why WR99210 is effective against pyrimethamine-resistant parasites (Yuthavong et al., 2012).

The current study prepared a combinatorial library of two hundred-seven compounds containing the two pharmacophores, such as para-amino-benzoic acid and 1,3,5-triazine. Then ten compounds were screened using molecular property filter analysis and molecular docking. These screened compounds were synthesized using a microwave synthesizer, and in vitro, antimalarial evaluations were performed in chloroquine-sensitive (3D7) and resistant (DD2) strains of P. falciparum.