The multicomponent Castagnoli-Cushman reaction followed by post-condensational modifications allowed for a flexible, modular construction of fluorescent chemosensor compounds. When tested against a panel of fourteen metal ions, one of the eight compounds investigated in this work was found to selectively respond to Cu²⁺ ions by fluorescence quenching (thus being a “turn-off” chemosensor for this metal). Another compound was found to produce fluorescence increase in response to Pb²⁺ ions. Interestingly, the sensitivity of this “turn-on” chemosensor to lead(II) ions was unaffected by the presence of a large excess of other metals. Analysis of the structure-sensing property relationships of these sensors allowed developing a general understanding of the factors influencing the chemosensor properties. All of the critical structural factors employed in the chemosensor design were found to be important for the metal sensing and selectivity. These findings will allow designing next-generation chemosensors based on the same modular construction approach in the future.