Since the drug is transported in aqueous media like blood and intracellular fluid, it has to be sufficiently water-soluble in the absolute sense (i.e. must have a minimum chemical solubility in order to be effective).
Natural toxins are used in pharmacological research to find out their mechanism of action, and if it could be exploited for beneficial purposes.
Alkylnitro compounds tend to be irritants, and Michael acceptors, such as enones, are alkylating agents and thus potentially mutagenic and carcinogenic.
Druglikeness can be estimated for any molecule, and does not evaluate the actual specific effect that the drug achieves (biological activity).
Simple rules are not always accurate and may unnecessarily limit the chemical space to search: many best-selling drugs have features that cause them to score low on various druglikeness indices.