A series of imidazole derivatives were designed following rational drug design, and synthesized through microwave-assisted one-pot multicomponent reactions. These compounds are produced in large quantities, and are known to be tolerant toward a variety of substrates, thus providing target molecules in a single step within a short time. These compounds were further tested for their ability to inhibit indoleamine-2,3-dioxygenase 1 (IDO1). The most promising compound thus obtained is 4o, which displayed IC 50 values of 0.82 μΜ. Further in vivo assessment indicated that 4o could reduce the kynurenine levels in plasma by 42.3% in 4 hr, indicating that the compound could act as a promising lead compound for further investigations. K E Y W O R D SIDO1 inhibitors, imidazole, microwave, one-pot