HIV infection remains a major medical problem, with approximately 38 million people worldwide living with HIV. Nipamovir and SAMT-247 are simple and inexpensive small molecules that inactivate HIV virus by interference with final maturation steps of the virus. This mechanism provides a high barrier for HIV to develop resistance. In fact, lab experiments designed to encourage HIV to develop resistance to Nipamovir and SAMT-247 have all failed. In animal tests, Nipamovir and SAMT-247 do not display toxic side effects. SAMT-247 is an effective microbicide that can be used to block HIV infection in animal models. Both Nipamovir and SAMT-247 are rapidly metabolized in blood where the sulfur of molecule is methylated, resulting in loss of antiviral activity. By attaching specific sidechains to the S-acylbenzamide scaffold of Nipamovir and SAMT-247, NIDDK investigators have developed new molecules that have improved anti-HIV activity and also are resistant to metabolism in blood.